Aberrant Cell Growth Research Articles

Cyclin D1 integrates G9a-mediated histone methylation

Lysine methylation of histones and non-histone substrates by the SET domain containing protein lysine methyltransferase (KMT) G9a/EHMT2 governs transcription contributing to apoptosis, aberrant cell growth, and pluripotency. The positioning of chromosomes within the nuclear three-dimensional space involves interactions between nuclear lamina (NL) and the lamina-associated domains (LAD). Contact of individual LADs with the NL are dependent upon H3K9me2 introduced by G9a. The mechanisms governing the recruitment of G9a to distinct subcellular sites, into chromatin or to LAD, is not known. The cyclin D1 gene product encodes the regulatory subunit of the holoenzyme that phosphorylates pRB and NRF1 thereby governing cell-cycle progression and mitochondrial metabolism. Herein, we show that cyclin D1 enhanced H3K9 dimethylation though direct association with G9a. Endogenous cyclin D1 was required for the recruitment of G9a to target genes in chromatin, for G9a-induced H3K9me2 of histones, and for NL-LAD interaction. The finding that cyclin D1 is required for recruitment of G9a to target genes in chromatin and for H3K9 dimethylation, identifies a novel mechanism coordinating protein methylation.

Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation

Fibroblasts are actively involved in the creation of the stroma and the extracellular matrix which are important for cell adhesion, cell–cell communication, and tissue metabolism. The role of fibrosis in carcinogenesis can be examined by analogy to tissues of various cancers. The orchestration of letters in the interplay of manifold components with signaling and crosstalk is incompletely understood but available evidence suggests a hitherto underappreciated role for fibrosis in carcinogenesis. Complex signaling and crosstalk by pathogenic stimuli evoke persistent subclinical inflammation, which in turn, results in a cascade of different cell types, ubiquitous proteins and their corresponding enzymes, cytokine releases, and multiple signaling pathways promoting the onset of fibrosis. There is considerable evidence that the body's attempt to resolve such a modified extracellular environment leads to further disruption of homeostasis and the genesis of the precancerous niche as part of the six-step process that describes carcinogenesis. The precancerous niche is formed and can be understood to develop as a result of (1) pathogenic stimulus, (2) chronic inflammation, and (3) fibrosis with alterations of the extracellular matrix, stromal rigidity, and mechano-transduction. This is why carcinogenesis is not just a process of aberrant cell growth with damaged genetic material but the role of the PCN in its entirety reveals how carcinogenesis can occur without invoking the need for somatic mutations.

Finding a cure for tuberous sclerosis complex: From genetics through to targeted drug therapies.

Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic condition caused by a mutation in either the TSC1 or TSC2 gene. Phenotypically, this leads to aberrant cell growth and the formation of benign tumors called hamartomas in multiple organs. Understanding the mechanisms of pathology that are caused through the presence of disease causing mutations is a real hurdle for many rare genetic disorders; a limiting factor that restricts knowledge of the disease and any hope of a future cure. Through the discovery of the TSC1 and TSC2 genes and the signaling pathways responsible for the pathology of TSC, a new drug target called mechanistic target of rapamycin complex 1 (mTORC1) was discovered. Rapamycin, an mTORC1 inhibitor, is now the only pharmacological therapy approved for the treatment of TSC. This chapter summarizes the success story of TSC and explores the future possibilities of finding a cure.

Mutations in SRSF2 Alter CSF3R Splicing in AML and Increase Expression of the V3 Variant Relative to V1

Three annotated splice variants for CSF3R, the gene encoding the receptor for granulocyte colony-stimulating factor (G-CSF) that critically regulates neutrophil production, have been described. Splice variant 1 (CSF3R-V1, also known as wild-type) is the most highly expressed and widely studied. Splice variant 4 (CSF3R-V4) is generated through use of cryptic 5' and 3' splice sites in the last exon of CSF3R, and produces a frame shift that results in early termination of the receptor. Increased expression of this splice variant has been reported in some patients with de novo AML. This splice variant induces a hyperproliferative phenotype and delayed receptor internalization by a mechanism similar to that reported in patients with severe congenital neutropenia transforming to AML with acquired CSF3R mutations. Although expression of the CSF3R-V3 splice variant was reported some 20 years ago in placenta, nothing is currently known about its expression in primary human hematopoietic cells. The CSF3R-V3 splice variant is generated through use of an alternate 3' splice acceptor site in the last intron that results in an in-frame insertion of 27 amino acids. Lack of a suitable assay to detect the CSF3R-V3 splice variant has limited studies of this variant.In order to detect and quantitate the three annotated CSF3R splice variants, we developed and validated a digital PCR method that permitted absolute quantitation of each splice variant. Using this assay, we initially quantitated expression of each variant in purified CD34+ cells, neutrophils, and monocytes from healthy donors. As shown in Table 1, CSF3R-V3 is expressed along with the CSF3R-V1 and CSF3R-V4 splice variants, and it comprises a significant proportion of the total CSF3R receptor in normal myeloid and progenitor cells. We next investigated the effect of co-expression of CSF3R-V3 and CSF3R-V1 to reproduce the in vivo situation. Ba/F3 clones expressing both the CSF3R-V3 and CSF3R-V1 variants were generated and G-CSF dose response and proliferation assays performed. Co-expression of both variants in the same cell induced G-CSF hypersensitivity and increased cell proliferation relative to cells expressing only CSF3R-V1.We next examined expression of the three CSF3R splice variants in primary cells from patients with AML. We were particularly interested in determining the effect of mutations in the SRSF2 gene that encodes a splicing factor frequently mutated in myeloid neoplasms. Using our digital PCR assay, expression of the three CSF3R splice variants was measured in purified CD34+ cells isolated from 11 patients with AML lacking mutations in splicing factor genes and compared to CD34+ cells isolated from 6 healthy donors. No significant differences were detected in the ratio of V3/V1 or the ratio of V4/V1 in AML cells compared to normal cells. Notably, when digital PCR was performed on CD34+ selected cells from 4 patients with AML with mutations in SRSF2, a statistically significant increase in the V3/V1 ratio was observed compared to CD34+ cells from patients with AML lacking mutations in splicing factor genes. These results suggest that SRSF2 regulates CSF3R splicing. Knockout of SRFS2 in HL-60 cells using CRISPR/Cas9 also resulted in an increased V3/V1 ratio, lending further support for a role of SRSF2 in CSF3R splicing and isoform expression.Collectively, we demonstrate for the first time expression of the CSF3R-V3 splice variant in primary human myeloid cells, and show that SRSF2 modulates CSF3R splicing. The observation that expression of CSF3R splice variants is altered in cells from patients with AML and SRSF2 mutations provides novel insights into the pathophysiologic mechanisms by which SRSF2 mutations contribute to aberrant cell growth and differentiation in AML. [Display omitted] DisclosuresAvalos:Juno: Membership on an entity's Board of Directors or advisory committees.

Acquisition of resistance to vemurafenib leads to interleukin-10 production through an aberrant activation of Akt in a melanoma cell line.

Serine/threonine-protein kinase B-Raf (BRAF) inhibitors are very effective in treating melanoma with BRAF mutations. BRAF inhibitors suppress aberrant growth of melanoma cells caused by BRAF mutations. BRAF mutations reportedly result in melanoma cells releasing immunosuppressive factors, and BRAF inhibitors elicit anti-melanomaimmune responses by reducing such factors. However, immunological characteristics of tumor cells that acquire resistance to BRAF inhibitors remain unknown. Here, we compared immunological characteristics between a melanoma cell line and its vemurafenib-resistant subline. No differences were observed in the status of BRAF mutations, expression of surface molecules related to antitumor T-cell responses or recognition by human leukocyte antigen-A*0201-matched melanoma-specific cytotoxic T lymphocytes in a short-term co-culture assay. However, resistant tumor cells released high amounts of interleukin-10 depending on aberrant activation of Akt signaling, and dendritic cell functions were considerably suppressed by culture supernatants of the resistant cells. Our findings demonstrated a novel immunological mechanism contributing to tumor growth owing to drug resistance to BRAF inhibitors.

RUNX2 Promotes Malignant Progression in Glioma.

Glioblastoma (GBM) is the most aggressive and lethal form of brain tumor. However, therapeutic strategies against malignant gliomas have not been completely established. Runt-related transcription factor 2 (Runx2) is an essential gene for skeletal development but its regulatory role in the malignant progression of glioma remains unclear. Here we investigated expression levels of RUNX2 in glioma tissues and its regulatory effects on aberrant growth of glioma cells. RUNX2 mRNA levels were higher in GBM tissues than that of normal brains or low-grade gliomas. RUNX2 protein was detected in five out of seven human GBM cell lines and its level was positively correlated with proliferative capacity. Stable transduction of dominant-negative Runx2 in rat-derived C6 glioma cells not only inhibited the promoter activity containing Runx2 response element, but also decreased mRNA expression levels of Runx2 target genes, such as Mmp13 and Spp1, as well as the proliferative capacity. Furthermore, transient introduction of Runx2-targeted siRNAs into C6 glioma cells significantly decreased mRNA expression levels of Mmp13 and Spp1 and the proliferative capacity. Furthermore, Runx2 knockdown suppressed both Ccnd1 mRNA expression and activation of the Ccnd1 promoter by forskolin, a PKA-activating reagent, in C6 glioma cells. Our results demonstrate that cross-talk between cAMP/PKA signaling and RUNX2 promotes a malignant phenotype of glioma cells.

Nanocarriers for the Effective Treatment of Cervical Cancer: Research Advancements and Patent Analysis.

Cervical cancer being the cancer of cervix is caused by an aberrant cell growth that acquires an ability to spread/ invade to other body parts. It has also been reported to be the second most common cause of death and cancer among women. Based on the severity of the disease, treatment aspects need to be explored more in order to overcome the limitations acquired by the conventional treatment. Recently, nanocarriers based drug delivery systems including liposomes, nanofibres, metallic NPs, polymeric NPs, dendrimers, polymeric micelles, antibody-drug conjugates, etc. have been explored to target and treat cervical cancer. This review highlights numerous recent research and patent reports as well on nanocarriers based systems. Patents viz US, EP and WIPO have been retrieved using sites www.uspto.gov/patft and www.freepatentsonline.com to collect literature on nanocarriers. Various research reports and patents revealed nanocarriers to be effective in treating cervical cancer and these carriers are observed to be safer than the conventional treatment. Nanocarriers result in transforming drug distribution that can overpower drug resistance. Further, nanocarriers based drug delivery systems can particularly target drugs to cellular, subcellular and tissue sites. By enhancing the drug's bioavailability at the desired site, these systems result in therapeutic benefits like enhanced safety and efficacy. Also, in combination with other treatment approaches like radiation, photothermal and gene therapy, nanocarriers are reported to be quite effective and can define novel strategies to combat cervical cancer.

RAP2 mediates mechanoresponses of the Hippo pathway.

Mammalian cells are surrounded by neighboring cells and extracellular matrix (ECM), which provide cells with structural support and mechanical cues that influence diverse biological processes1. The Hippo pathway effectors YAP and TAZ are regulated by mechanical cues and mediate cellular responses to ECM stiffness2,3. Here we identified Ras-related GTPase RAP2 as a critical intracellular signal transducer that relays ECM rigidity signals to control mechano-sensitive cellular activities through YAP/TAZ. RAP2 is activated by low ECM stiffness, and RAP2 deletion blocks YAP/TAZ regulation by stiffness signals and promotes aberrant cell growth. Mechanistically, matrix stiffness acts through phospholipase Cγ1 (PLCγ1) to influence levels of phosphatidylinositol 4,5-bisphosphate (PIP2) and its product phosphatidic acid (PA), which activates RAP2 through PDZGEF1/2. At low stiffness, active RAP2 binds to and stimulates mitogen-activated protein kinase kinase kinase kinase 4/6/7 (MAP4K4/6/7) and Rho GTPase activating protein 29 (ARHGAP29), resulting in LATS1/2 activation and YAP/TAZ inhibition. RAP2 and YAP/TAZ play pivotal roles in mechano-regulated transcription, as YAP/TAZ deletion abolishes the ECM stiffness-responsive transcriptome. Our findings reveal RAP2 as a molecular switch in mechanotransduction, thereby defining a mechanosignaling pathway from ECM stiffness to the nucleus.

PO-243 Uncoupling FOXO3A mitochondrial and nuclear functions in cancer cells undergoing metabolic stress and chemotherapy

IntroductionWhile aberrant cancer cell growth is frequently associated with altered biochemical metabolism, normal mitochondrial functions are usually preserved and necessary for full malignant transformation. The transcription factor FoxO3A is a key determinant of cancer cell homeostasis, playing a dual role in survival/death response. We recently described a novel mitochondrial arm of the AMPK-FoxO3A axis in normal cells upon nutrient shortage.Material and methodsAfter extensive characterisation of mitochondrial FoxO3A function in vitro in several cell lines and tumours, we generated FoxO3A-knockout cancer cells with the CRISPR/Cas9 system and reconstituted FoxO3A expression with wild-type or mutant vectors.Results and discussionsHere we show that in metabolically stressed cancer cells, FoxO3A is recruited to the mitochondria through activation of MEK/ERK and AMPK which phosphorylate serine 12 and 30, respectively, on FoxO3A N-terminal domain. Subsequently, FoxO3A is imported and cleaved to reach mitochondrial DNA, where it activates expression of the mitochondrial genome to support mitochondrial metabolism and cell survival. Using FoxO3A-/- cancer cells generated with the CRISPR/Cas9 genome editing system and reconstituted with FoxO3A mutants being impaired in their nuclear or mitochondrial subcellular localization, we show that mitochondrial FoxO3A promotes survival in response to metabolic stress.In cancer cells treated with chemotherapeutic agents, accumulation of FoxO3A into the mitochondria promoted survival in a MEK/ERK-dependent manner, while mitochondrial FoxO3A was required for apoptosis induction by metformin.ConclusionElucidation of FoxO3A mitochondrial vs. nuclear functions in cancer cell homeostasis might help devise novel personalised therapeutic strategies to selectively disable FoxO3A pro-survival activity and manipulate cellular metabolism to counteract cancer initiation and progression.

Identification of a Pyranocoumarin Photosensitizer that is a Potent Inhibitor of Keratinocyte Growth.

Photosensitizers are used in the treatment of epidermal proliferation and differentiation disorders such as psoriasis and vitiligo. In these studies, a ring-expanded carbon homolog ofthe linear psoralen (furo[3,2-g]benzopyran-7-one) class ofphotosensitizers, 4,10-dimethyl-2H,8H-benzo[1,2-b:5,4-b']dipyran-2-one (NDH2476), was synthesized and analyzed for biological activity. Following activation by ultraviolet light (UVA, 320-400nm), NDH2476 was found to be a potent inhibitor of keratinocyte growth (IC50 =9nm). Similar derivatives methylated in the pyran ring, or containing a saturated pyran ring structure, were markedly less active or inactive as photosensitizers. NDH2476 was found to intercalate and damage DNA following UVA light treatment as determined by plasmid DNA unwinding and nicking experiments. Taken together, these data demonstrate that an intact furan ring in psoralen photosensitizers is not required for keratinocyte growth inhibition or DNA damage. Our findings that low nanomolar concentrations of a benzopyranone derivative were active as a photosensitizer indicates that this or a structurally related compound may be useful in the treatment of skin diseases involving aberrant epidermal cell growth and differentiation.

O-GlcNAcylation of the Tumor Suppressor FOXO3 Triggers Aberrant Cancer Cell Growth.

Posttranslational modifications of tumor suppressors can induce abnormal cell growth. Here, we identify site-specific O-GlcNAcylation as a critical block of FOXO3 that may abrogate a part of the p53 pathway, resulting in aberrant cancer cell growth. Of seven O-GlcNAcylation sites identified within the FOXO3 transactivation domain, we found that changes in O-GlcNAcylation at Ser284 modulated p21-mediated cancer cell growth. Overexpression of either O-GlcNAcylated FOXO3 (FOX-OV) or a Ser-to-Ala mutant (S284A) in PANC-1 cells indicated that S284 O-GlcNAc acts as a critical block of the FOXO tumor suppressor and induces proliferation in PANC-1 cancer cells by stimulating the MDM2-p53-p21 axis. Furthermore, S284A mutant cells lacking S284 O-GlcNAc and FOX-OV cells exhibited opposing MDM2-p53-p21 axis expression patterns at both the mRNA and protein levels. Thus, our study provides evidence to support a role for S284 O-GlcNAc as a critical block of FOXO3 to induce subsequent cancer cell growth via abrogation of the p53 regulatory circuit.Significance: These findings highlight a posttranslational mechanism for indirect abrogation of the p53 pathway, one that may occur with some frequency in human cancer cells. Cancer Res; 78(5); 1214-24. ©2018 AACR.

Abstract P5-21-19: Suppression of breast carcinogenesis and metastasis by targeting glucose metabolism with HJC0152

Abstract Lack of targeted strategies for preventing and treating estrogen receptor (ER)-negative breast cancer (ENBC) is an unmet clinical challenge. ENBCs including triple-negative BCs (TNBC) constitute 30-40% of BC cases and are prone to develop remote metastasis and local recurrence, resulting in the majority of deaths in BC patients. Dysregulated glucose and energy metabolism is critically involved in the development and progression of various cancers via promoting aberrant cell growth, malignant transformation and metastasis. Nevertheless, the potential role of glucose/energy metabolism in ENBC carcinogenesis has sparsely been explored, thus representing a key knowledge gap and a potential avenue for effective targeted therapies. Despite a substantial amount of effort has been made towards anticancer metabolic and biogenetic medications, none has progressed into clinical use, due to their limited potency, specificity or drug properties such as toxicity and poor bioavailability. We recently developed HJC0152, a novel small molecule anticancer agent, using structure- and fragment-based drug design strategies and molecular modeling techniques in our initial attempt to develop non-peptide STAT3 inhibitors for anticancer use. HJC0152 significantly inhibits proliferation of BC cells, induces apoptosis, reduces ER-negative mammary tumor development, suppresses ENBC xenograft tumor growth, and blocks lung metastasis in vivo. Intriguingly, HJC0152 differentially modulates expression of glycolytic enzymes including HK1, PFK-L, PFKFB2, ENO2, PDH, PDK1, PGAM1 and ALDOA in a time-dependent manner. HJC0152 also regulates the transcription of genes involved in glucose and mitochondrial energy metabolism, including the subunits of mitochondrial respiratory chain complexes. Functional assessments further demonstrate that HJC0152 significantly modulates respiratory chain complex function. Via in silico and Unique Polymer Technology (UPT) strategy, we identified a number of putative HJC0152-interacting targets for validation studies. Our findings suggest that HJC0152 is capable of reprogramming/restoring the dysregulated glucose metabolism by inducing specific glycolytic enzyme expression and mitochondrial respiratory chain function, likely via targeting upstream key signal molecule(s) that regulates glucose and energy metabolism, thereby suppressing breast cancer development and progression to metastasis. This work was supported by Grants P50 CA097007, and P30DA028821 (JZ) from the NIH, CPRIT (JZ), John Sealy Memorial Endowment Fund (JZ), DFI Grants from MD Anderson Cancer Center (QS), Holden Family Research Grant in BC Prevention (QS), and NCI PREVENT Program HHSN26100002 (QS). Citation Format: Dong J, Kim H, Xu J, Li D, Zhang Z, Zheng Z, Ye N, Chen H, Zhou J, Shen Q. Suppression of breast carcinogenesis and metastasis by targeting glucose metabolism with HJC0152 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-19.

Uncoupling FoxO3A mitochondrial and nuclear functions in cancer cells undergoing metabolic stress and chemotherapy

While aberrant cancer cell growth is frequently associated with altered biochemical metabolism, normal mitochondrial functions are usually preserved and necessary for full malignant transformation. The transcription factor FoxO3A is a key determinant of cancer cell homeostasis, playing a dual role in survival/death response to metabolic stress and cancer therapeutics. We recently described a novel mitochondrial arm of the AMPK-FoxO3A axis in normal cells upon nutrient shortage. Here, we show that in metabolically stressed cancer cells, FoxO3A is recruited to the mitochondria through activation of MEK/ERK and AMPK, which phosphorylate serine 12 and 30, respectively, on FoxO3A N-terminal domain. Subsequently, FoxO3A is imported and cleaved to reach mitochondrial DNA, where it activates expression of the mitochondrial genome to support mitochondrial metabolism. Using FoxO3A−/− cancer cells generated with the CRISPR/Cas9 genome editing system and reconstituted with FoxO3A mutants being impaired in their nuclear or mitochondrial subcellular localization, we show that mitochondrial FoxO3A promotes survival in response to metabolic stress. In cancer cells treated with chemotherapeutic agents, accumulation of FoxO3A into the mitochondria promoted survival in a MEK/ERK-dependent manner, while mitochondrial FoxO3A was required for apoptosis induction by metformin. Elucidation of FoxO3A mitochondrial vs. nuclear functions in cancer cell homeostasis might help devise novel therapeutic strategies to selectively disable FoxO3A prosurvival activity.

Opportunities and Challenges in Genomic Sequencing for Precision Cancer Care.

Cancer is defined by diverse somatic and germline alterations that promote aberrant cell growth. Tumor genomic profiling to guide therapy is now part of standard management in several solid tumor t...

Towards understanding the mechanisms of actions of carcinoembryonic antigen-related cell adhesion molecule 6 in cancer progression.

Human carcinoembryonic antigen (CEA) is the prototypic member of a family of highly related cell surface glycoproteins that includes carcinoembryonic antigen‐related cell adhesion molecule 6 (CEACAM6) and others. CEACAM6 (formerly NCA), which belongs to the immunoglobulin superfamily, is a cell adhesion protein of the CEA family. It is normally expressed on the epithelial surfaces and on the surface of myeloid cells (CD66c). CEACAM6 is a multi‐functional glycoprotein that mediates homotypic binding with other CEA family members and heterotypic binding with integrin receptors. It functions by organizing tissue architecture and regulating different signal transduction, while aberrant expression leads to the development of human malignancies. It was first discovered in proliferating cells of adenomas and hyperplastic polyps in comparison to benign colonic tissue when overexpressed on the surface of various cell types in model systems. CEACAM6 functions as a pan‐inhibitor of cell differentiation and cell polarization, and it also causes distortion of tissue architecture. Moreover, overexpression of CEACAM6 modulates cancer progression through aberrant cell differentiation, anti‐apoptosis, cell growth and resistance to therapeutic agents. In addition, CEACAM6 overexpression in multiple malignancies promotes cell invasion and metastasis, thereby representing an acquired advantage of tumor cells directly responsible for an invasive phenotype. This review focuses on the findings supporting the mechanisms of actions linking the oncogenic potential of CEACAM6 to the onset of cancer progression and pathogenesis, especially in breast cancer, and to validating CEACAM6 as a target to pave the way towards the design of efficient therapeutic strategies against breast cancer.

The tumor suppressor phosphatase PP2A-B56α regulates stemness and promotes the initiation of malignancies in a novel murine model.

Protein phosphatase 2A (PP2A) is a ubiquitously expressed Serine-Threonine phosphatase mediating 30–50% of protein phosphatase activity. PP2A functions as a heterotrimeric complex, with the B subunits directing target specificity to regulate the activity of many key pathways that control cellular phenotypes. PP2A-B56α has been shown to play a tumor suppressor role and to negatively control c-MYC stability and activity. Loss of B56α promotes cellular transformation, likely at least in part through its regulation of c-MYC. Here we report generation of a B56α hypomorph mouse with very low B56α expression that we used to study the physiologic activity of the PP2A-B56α phosphatase. The predominant phenotype we observed in mice with B56α deficiency in the whole body was spontaneous skin lesion formation with hyperproliferation of the epidermis, hair follicles and sebaceous glands. Increased levels of c-MYC phosphorylation on Serine62 and c-MYC activity were observed in the skin lesions of the B56αhm/hm mice. B56α deficiency was found to increase the number of skin stem cells, and consistent with this, papilloma initiation was accelerated in a carcinogenesis model. Further analysis of additional tissues revealed increased inflammation in spleen, liver, lung, and intestinal lymph nodes as well as in the skin lesions, resembling elevated extramedullary hematopoiesis phenotypes in the B56αhm/hm mice. We also observed an increase in the clonogenicity of bone marrow stem cells in B56αhm/hm mice. Overall, this model suggests that B56α is important for stem cells to maintain homeostasis and that B56α loss leading to increased activity of important oncogenes, including c-MYC, can result in aberrant cell growth and increased stem cells that can contribute to the initiation of malignancy.

LSD1, a double-edged sword, confers dynamic chromatin regulation but commonly promotes aberrant cell growth.

Histone-modifying enzymes play a critical role in chromatin remodeling and are essential for influencing several genome processes such as gene expression and DNA repair, replication, and recombination. The discovery of lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, dramatically revolutionized research in the field of epigenetics. LSD1 plays a pivotal role in a wide range of biological operations, including development, cellular differentiation, embryonic pluripotency, and disease (for example, cancer). This mini-review focuses on the role of LSD1 in chromatin regulatory complexes, its involvement in epigenetic changes throughout development, and its importance in physiological and pathological processes.

Expression of Truncated Neurokinin-1 Receptor in Childhood Neuroblastoma is Independent of Tumor Biology and Stage.

Neuroblastoma is an embryonal malignancy arising from the aberrant growth of neural crest progenitor cells of the sympathetic nervous system. The tachykinin receptor 1 (TACR1) - substance P complex is associated with tumoral angiogenesis and cell proliferation in a variety of cancer types. Inhibition of TACR1 was recently described to impede growth of NB cell lines. However, the relevance of TACR1 in clinical settings is unknown. We investigated gene expression levels of full-length and truncated TACR1 in 59 neuroblastomas and correlated these data with the patients' clinical parameters such as outcome, metastasis, International Neuroblastoma Staging System (INSS) status, MYCN proto-oncogene, bHLH transcription factor (MYCN) status, gender and age. Our results indicated that TACR1 is ubiquitously expressed in neuroblastoma but expression levels are independent of clinical parameters. Our data suggest that TACR1 might serve as a potent anticancer target in a large variety of patients with neuroblastoma, independent of tumor biology and clinical stage.

Genetic deletion of Rnd3 in neural stem cells promotes proliferation via upregulation of Notch signaling.

Rnd3, a Rho GTPase, is involved in the inhibition of actin cytoskeleton dynamics through the Rho kinase-dependent signaling pathway. We previously demonstrated that mice with genetic deletion of Rnd3 developed a markedly larger brain compared with wild-type mice. Here, we demonstrate that Rnd3 knockout mice developed an enlarged subventricular zone, and we identify a novel role for Rnd3 as an inhibitor of Notch signaling in neural stem cells. Rnd3 deficiency, both in vivo and in vitro, resulted in increased levels of Notch intracellular domain protein. This led to enhanced Notch signaling and promotion of aberrant neural stem cell growth, thereby resulting in a larger subventricular zone and a markedly larger brain. Inhibition of Notch activity abrogated this aberrant neural stem cell growth.

Regulation of PI3K effector signalling in cancer by the phosphoinositide phosphatases.

Class I phosphoinositide 3-kinase (PI3K) generates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) at the plasma membrane in response to growth factors, activating a signalling cascade that regulates many cellular functions including cell growth, proliferation, survival, migration and metabolism. The PI3K pathway is commonly dysregulated in human cancer, and drives tumorigenesis by promoting aberrant cell growth and transformation. PtdIns(3,4,5)P3 facilitates the activation of many pleckstrin homology (PH) domain-containing proteins including the serine/threonine kinase AKT. There are three AKT isoforms that are frequently hyperactivated in cancer through mutation, amplification or dysregulation of upstream regulatory proteins. AKT isoforms have converging and opposing functions in tumorigenesis. PtdIns(3,4,5)P3 signalling is degraded and terminated by phosphoinositide phosphatases such as phosphatase and tensin homologue (PTEN), proline-rich inositol polyphosphate 5-phosphatase (PIPP) (INPP5J) and inositol polyphosphate 4-phosphatase type II (INPP4B). PtdIns(3,4,5)P3 is rapidly hydrolysed by PIPP to generate phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2), which is further hydrolysed by INPP4B to form phosphatidylinositol 3-phosphate (PtdIns3P). PtdIns(3,4)P2 and PtdIns3P are also important signalling molecules; PtdIns(3,4)P2 together with PtdIns(3,4,5)P3 are required for maximal AKT activation and PtdIns3P activates PI3K-dependent serum and glucocorticoid-regulated kinase (SGK3) signalling. Loss of Pten, Pipp or Inpp4b expression or function promotes tumour growth in murine cancer models through enhanced AKT isoform-specific signalling. INPP4B inhibits PtdIns(3,4)P2-mediated AKT activation in breast and prostate cancer; however, INPP4B expression is increased in acute myeloid leukaemia (AML), melanoma and colon cancer where it paradoxically promotes cell proliferation, transformation and/or drug resistance. This review will discuss how PTEN, PIPP and INPP4B distinctly regulate PtdIns(3,4,5)P3 signalling downstream of PI3K and how dysregulation of these phosphatases affects cancer outcomes.