Proteostasis Deregulation by Metabolism Drives the Hallmarks of Cancer.

Lysine methyltransferase 5a (KMT5a) plays a key role in the pathogenesis of many human diseases. Here, we review the diverse impacts of KMT5a activity on human cancer development and progression. First, KMT5a is the only Mammalian enzyme that specifically induces monomethylation of histone 4 (H4) on lysine 20, thus regulating chromatin organization and, in turn, the transcription of several oncogenes and tumor suppressor genes. KMT5a, by inducing H4 methylation, also critically establishes the choice between different pathways of DNA double-strand break repair, with important consequences for genomic instability and cancer origin. Finally, KMT5a also methylates lysine residues on nonhistone proteins, and KMT5a-induced methylation of key oncogenic and tumor suppressor proteins, including TP53, strongly affects cancer cell functions. Overall, KMT5a is overexpressed in a high percentage and wide variety of human cancers and has protumorigenic activity, which makes it a target for innovative therapy.

The interaction of SET and protein phosphatase 2A as target for cancer therapy

The apoptosis stimulating proteins of p53 (ASPP) are important regulatory proteins of p53 family, consisting of ASPP1, ASPP2 and iASPP. ASPP combine with p53 ,and ASPP1 and ASPP2 promote cell apoptosis of p53 specifically,where as iASPP inhibit the tumor suppressing function of p53 by combining with p53. Thus,ASPP family of proteins,especially iASPP, may be a novel target for cancer therapy. Key words: Tumor suppressor protein p53; Apoptosis; Apoptosis stimutating protein of p53

The causes of cancer revisited: “Mitochondrial malignancy” and ROS-induced oncogenic transformation – Why mitochondria are targets for cancer therapy

Protooncogene- and tumor-suppressor gene proteins serve essential functions in the regulation of proliferation and differentiation of cells. Abnormal regulation or mutation of these genes, or transformation with retroviral homologs, may lead to tumor development in animals. In contrast to vertebrates, only few data on these genes exist in plants and fungi. Plant nuclear protooncogene homologs, such as myb and myc have multiple regulatory functions in metabolic pathways not existing in mammalian cells; they are involved in the complex regulation of anthocyanin (purple pigment) and phlobaphene (red pigment) biosynthesis, lignin production, trichome differentiation, dehydration stress gene expression and seed development. Apart from these well-characterized roles in plant-specific pathways, few experimental data have been reported on a functional significance in growth and development. A screening for nuclear protooncogene- and tumor-suppressor gene-related proteins in the myxomycete Physarum polycephalum revealed the existence of homologs of vertebrate c-myc, c-fos, c-jun, p53, and retinoblastoma proteins during the synchronous cell cycle or sclerotization. The p53 homologs of Physarum and Zea mays were shown to be specific for quiescent stages of their life cycles. Plants and lower eukaryotes, such as fungi, may be useful experimental systems to elucidate novel functions of protooncogene- and tumor-suppressor proteins in cell cycle regulation and development, or to reveal target genes that might be difficult to identify in complex mammalian systems. Recent data indicate that oncogenes and tumor suppressors in animals have more cellular targets than originally proposed; some of these might be as unexpected as in plant secondary metabolism.

High grade serous ovarian cancer (HGSC), the most common subtype of epithelial ovarian cancer carries a grim prognosis with about 50% 5-year overall survival rates with modern therapies. Chemotherapy and surgery are still the most important modalities of HGSC treatment and very few targeted therapies are available. Thus, better understanding of molecular pathways and potential targets driving HGSC is key to developing novel therapeutics. Here we study coiled-coil domain containing 80 proteins (CCDC80), also known as DRO1. Little is known about the role of CCDC80 in health and disease. Previous studies have reported that CCDC80 expressed in fibroblasts may act as a tumor suppressor protein. We hypothesized that CCDC80 has a tumor cell intrinsic tumor suppressive role in HGSC. To address this, we performed in vitro cancer cell-based assays including proliferation, apoptosis, migration, and colony formation following CCDC80 knockdown and overexpression in several HGSC cell lines. We found that in cancer cells, CCDC80 plays tumor suppressive roles through inhibiting cell migration and colony formation. CCDC80 is known to be down regulated by oncogenes, and we have found that CCDC80 is transcriptionally down regulated by PAX8, a fallopian tube lineage marker that is an oncogenic master regulator of transcription in this disease. The negative regulation of CCDC80 mediates the oncogenic roles of PAX8 on cell migration and colony formation. Of note, consistent with its role as a lineage marker, PAX8 is also expressed in benign fallopian tube cells, the cell of origin of HGSC, but in fallopian tube cells PAX8 does not regulate CCDC80 and therefore does not play an oncogenic role. To understand the mechanism of the tumor suppressive capabilities of CCDC80, we overexpressed CCDC80 in HGSC cells and performed mass spectrometry to identify differentially expressed proteins. One of the most downregulated proteins upon CCDC80 overexpression was the transmembrane immune checkpoint protein B7-H3, which is currently a target for cancer therapy in clinical development stages. We found that in HGSC, B7-H3 is repressed by CCDC80 and activated by PAX8, and has tumor cell-intrinsic oncogenic capacities, including an anti-apoptotic, a pro-clonogenic and a pro-migratory role. We postulate that there is a correlation between the subcellular localization and the functional role of B7-H3. While the well-known role of B7-H3 as an immune checkpoint protein is mediated by the trans-membranous protein and its extra-cellular domain, in HGSC B7-H3 is intra-cellular, localized to the cellular cytoplasm, and plays tumor cell intrinsic oncogenic roles. Taken together, we reveal a new HGSC tumor suppressor protein, and show its regulation and mode of action. The PAX8/CCDC80/B7-H3 which regulates several oncogenic functions in HGSC could potentially serve in the future as a target for drug development. Citation Format: Aya Saleh, Basem Fares, Lina Korsensky, Liron Berger, Ruth Perets. CCDC80 as a novel cell intrinsic tumor suppressor protein in high grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B015.

Inhibitors of the HSP90 Molecular Chaperone: Current Status

Antitumor effects of berberine against EGFR, ERK1/2, P38 and AKT in MDA-MB231 and MCF-7 breast cancer cells using molecular modelling and in vitro study

The anti-tumor action of engineered mesenchymal stem cells highlights the double-edged role of oncoproteins in osteosarcoma, and suggests the possibility of developing a novel strategy for protein-based cancer therapy.

Base excision repair (BER) is a frontline system that is responsible for maintaining genome integrity and thus preventing premature aging and cancer by repairing DNA lesions and strand breaks caused by endogenous and exogenous mutagens. However, it is also the principal cellular system in cancer cells that counteracts the killing effect of the major cancer treatments, e.g. chemotherapy and ionizing radiation. Although it is clear that an individual's DNA repair capacity varies, the mechanisms involved in the regulation of repair systems responsible for such variations is only just emerging. This knowledge gap is impeding the finding of new cancer therapy targets and the development of novel treatment strategies. In recent years the vital role of post-translational modifications of BER proteins, including ubiquitylation, has been uncovered. Interestingly, new players in the regulation of BER include proteins encoded by well-known tumour suppressors. This review covers recent progress in our understanding of the post-translational regulation of BER, including the proteins involved, with a specific focus on the role of the ARF (p14) tumour suppressor protein in BER.

Cyclin E-Cdk2 is essential for S phase entry. To identify genes interacting with cyclin E, we carried out a genetic screen using a hypomorphic mutation of Drosophila cyclin E (DmcycE(JP)), which gives rise to adults with a rough eye phenotype. Amongst the dominant suppressors of DmcycE(JP), we identified brahma (brm) and moira (mor), which encode conserved core components of the Drosophila Brm complex that is highly related to the SWI-SNF ATP-dependent chromatin remodeling complex. Mutations in genes encoding other Brm complex components, including snr1 (BAP45), osa and deficiencies that remove BAP60 and BAP111 can also suppress the DmcycE(JP) eye phenotype. We show that Brm complex mutants suppress the DmcycE(JP) phenotype by increasing S phases without affecting DmcycE protein levels and that DmcycE physically interacts with Brm and Snr1 in vivo. These data suggest that the Brm complex inhibits S phase entry by acting downstream of DmcycE protein accumulation. The Brm complex also physically interacts weakly with Drosophila retinoblastoma (Rbf1), but no genetic interactions were detected, suggesting that the Brm complex and Rbf1 act largely independently to mediate G(1) arrest.

Tumor progression and metastasis depend on the ability of cancer cells to initiate angiogenesis to ensure delivery of oxygen, nutrients, and growth factors to tumor cells and provide access to the systemic circulation. Hypoxia-inducible factor-1 (HIF-1) can activate expression of a broad range of genes that mediate many of the adaptive responses to decreased oxygen concentration, such as enhanced glucose uptake and formation of new blood vessels. Acting through Plexin-B1 on endothelial cells, Semaphorin 4D (Sema4D) has been shown to promote angiogenesis and enhance invasive growth and proliferation in some tumors. Here we show that the gene for Sema4D, the product of which is elevated in head and neck squamous cell carcinoma (HNSCC) cells, contains upstream hypoxia response elements (HRE) and is strongly induced in hypoxia in a HIF-1-dependent manner. Knocking down Sema4D expression with short hairpin (sh) RNA reduces in vitro endothelial cell migration and growth and vascularity of HNSCC xenografts expressing a degradation resistant HIF-1alpha subunit. We also demonstrate a correlation between HIF-1 activity and Sema4D expression in HNSCC specimens. These findings indicate that Sema4D is induced by hypoxia in a HIF-1-dependent manner and influences endothelial cell migration and tumor vascularity. Expression of Sema4D may be a strategy by which carcinomas promote angiogenesis and therefore could represent a therapeutic target for these malignancies.

Matrix metalloproteinases (MMPs) have long been linked to cancer progression owing to their ability to breakdown tissue barriers for metastatic spread. Accordingly, multiple studies have examined the potential value of these enzymes as targets for cancer therapy. Unfortunately, most clinical trials with MMP inhibitors have yielded negative results which has made necessary to re-evaluate the role of these proteases in cancer. Recent works mainly based on the use of mouse models deficient in specific MMPs have revealed that these enzymes play many roles in cancer distinct from matrix destruction, influencing early steps of tumor evolution, and expanding their pro-tumorigenic properties. However, these in vivostudies have also shown that, unexpectedly, some MMP family members like MMP8 may have paradoxical anti-tumor functions. Nevertheless, the final validation of these MMPs as bona fide tumor suppressors requested the identification of the putative genetic or epigenetic changes underlying their inactivation during cancer development. To this purpose, very recent large-scale genomic studies have explored the possibility that MMPs could be genetically altered in a panel of human malignant tumors from different sources. These studies have demonstrated that MMP8 is a frequently mutated gene in human melanoma. Functional analysis of the identified mutations has confirmed that all of them lead to the loss-of-function of MMP8 and enhance the progression of melanoma, thus providing definitive evidence that MMP8 is a tumor-suppressor gene. Parallel studies have extended these findings to other MMP-related metalloproteinases such as ADAMTS15, which has been found to be genetically inactivated in human colorectal cancer. This review describes the identification and validation of some MMPs and related enzymes as anti-tumor proteases and speculates about the molecular mechanisms underlying their protective roles in tumor development. Finally, the review explores the clinical applications derived from the identification of MMPs that favor the host instead of the tumor.

Background: The uncontrolled growth due to accumulation of genetic and epigenetic changes as a result of loss or reduction in the normal function of Tumor Suppressor Genes (TSGs) and Pro-oncogenes is known as cancer. TSGs control cell division and growth by repairing of DNA mistakes during replication and restrict the unwanted proliferation of a cell or activities, those are the part of tumor production. Objectives: This study aims to propose a novel, accurate, user-friendly model to predict tumor suppressor proteins, which would be freely available to experimental molecular biologists to assist them using in vitro and in vivo studies. Methods: The predictor model has used the input feature vector (IFV) calculated from the physicochemical properties of proteins based on FCNN to compute the accuracy, sensitivity, specificity, and MCC. The proposed model was validated against different exhaustive validation techniques i.e. self-consistency and cross-validation. Results: Using self-consistency, the accuracy is 99%, for cross-validation and independent testing has 99.80% and 100% accuracy respectively. The overall accuracy of the proposed model is 99%, sensitivity value 98% and specificity 99% and F1-score was 0.99. Conclusion: It concludes, the proposed model for prediction of the tumor suppressor proteins can predict the tumor suppressor proteins efficiently, but it still has space for improvements in computational ways as the protein sequences may rapidly increase, day by day.

Anticancer agents that counteract tumor glycolysis.