Actin-like 6A Research Articles

Actin like 6A is a prognostic biomarker and associated with immune cell infiltration in cancers

PurposeTo investigate the role of Actin like 6 A (ACTL6A) in cancer and explore the potential mechanism of its function.MethodsDifferential expression of ACTL6A was analyzed using Oncomine and TIMER database. Then, we downloaded data sets from TCGA database. The correlation between ACTL6A expression and survival in pan-cancer were analyzed by “survival”, “survminer” R package and PrognoScan database. STRING (v 11.0) and stringAPP for Cytoscape v3.7.2 were used to predict ACTL6A associated genes. Copy number and methylation alterations of ACTL6A were analyzed using cBioPortal and GSCALite. Transcription factors were downloaded from The Human Transcription Factors Database and analyzed using “limma” R package, JASPAR and PROMO database. Correlations analysis between ACTL6A and immune cells were performed using TIMER and GEPIA database.ResultsIn our studies, we found that ACTL6A was widely upregulated in cancers, which might be attributed to its gene amplifications. Moreover, ACTL6A might regulated by transcription factors (TFs), including E2F1, YY1, CDX2 and HOXD10. In addition, high ACTL6A expression was associated with poor prognosis in most cancers. Meanwhile, ACTL6A was associated with the infiltration of immune cells, especially in liver hepatocellular carcinoma and brain lower grade glioma.ConclusionAmplification of ACTL6A is correlated with poor prognosis and contribute to immune cells infiltration in LIHC and LGG, which may provide immune-related therapeutic targets to guide clinical strategies.

Circ_0084615 promotes epithelial-mesenchymal transition-mediated tumor progression in hepatocellular carcinoma.

CircRNAs have been identified as crucial regulators in tumorigenesis and progression. This study aimed to explore the biological role and underlying mechanism of circ_0084615 in hepatocellular carcinoma (HCC). The expression of RNAs was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The effects of circ_0084615 silencing on malignant behaviors of HCC cells were assessed by CCK-8, colony formation, wound healing, and Transwell assays invitro and tumor transplantation experiment invivo. The expression of proteins was detected by Western blotting. Dual-luciferase reporter assay and RNA-binding protein immunoprecipitation were performed to explore the mechanism of circ_0084615. A significant upregulation of circ_0084615 was observed in HCC tissues, and positively correlated with the TNM staging. Silencing of circ_0084615 impeded HCC cell viability, colony formation, migration, invasion, epithelial-mesenchymal transition, and xenograft tumor growth. Mechanistically, circ_0084615 could bind to miR-1200 and eliminate its ability to destroy actin-like 6A (ACTL6A) mRNA, thereby increasing ACTL6A expression and facilitating the malignant behaviors of HCC cells. This study clarified the oncogenic activity and mechanism of circ_0084615, thereby providing potential diagnostic biomarker and therapeutic target for inhibiting HCC progression.

Discovery of a proliferation essential gene signature and actin-like 6A as potential biomarkers for predicting prognosis and neoadjuvant chemotherapy response in triple-positive breast cancer.

Patients with triple-positive breast cancer (TPBC) have a higher risk of recurrence and lower survival rates than patients with other luminal breast cancers. However, there are few studies on the predictive biomarkers of prognosis and treatment responses in TPBC. Proliferation essential genes (PEGs) were acquired from clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) technology, and cohorts of patients with TPBC were obtained from public databases and our cohort. To develop a TPBC-PEG signature, Cox regression and least absolute shrinkage and selection operator regression analyses were applied. Functional analyses were performed with gene set enrichment analysis. The relationship between candidate genes and neoadjuvant chemotherapy (NACT) sensitivity was explored via real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) on the basis of clinical samples. Among 900 TPBC-PEGs, 437 showed significant differential expression between TPBC and normal tissues. Three prognostic PEGs (actin-like 6A [ACTL6A], chaperonin containing TCP1 subunit 2 [CCT2], and threonyl-TRNA synthetase [TARS]) were identified and used to construct the PEG signature. Patients with high PEG signature scores exhibited a worse overall survival and lower sensitivity to NACT than patients with low PEG signature scores. RT-qPCR results indicated that ACTL6A and CCT2 expression were significantly upregulated in patients who lacked sensitivity to NACT. IHC results showed that the ACTL6A protein was highly expressed in patients with NACT resistance and nonpathological complete responses. This efficient PEG signature prognostic model can predict the outcomes of TPBC. Furthermore, ACTL6A expression level was associated with the response to NACT, and could serve as an important factor in predicting prognosis and drug sensitivity of patients with TPBC.

ACTL6A: unraveling its prognostic impact and paving the way for targeted therapeutics in carcinogenesis.

Introduction: Increased Actin-like 6A (ACTL6A) expression is associated with various cancers, but its comprehensive investigation across different malignancies is lacking. We aimed to analyze ACTL6A as a potential oncogene and therapeutic target using bioinformatics tools. Methods: We comprehensively analyzed ACTL6A expression profiles across human malignancies, focusing on correlations with tumor grade, stage, metastasis, and patient survival. Genetic alterations were examined, and the epigenetic landscape of ACTL6A was assessed using rigorous methods. The impact of ACTL6A on immune cell infiltration in the tumor microenvironment was evaluated, along with molecular docking studies and machine learning models. Results: Our analysis revealed elevated ACTL6A expression in various tumors, correlating with poor prognostic indicators such as tumor grade, stage, metastasis, and patient survival. Genetic mutations and epigenetic modifications were identified, along with associations with immune cell infiltration and key cellular pathways. Machine learning models demonstrated ACTL6A's potential for cancer detection. Discussion: ACTL6A emerges as a promising diagnostic and therapeutic target in cancer, with implications for prognosis and therapy. Our study provides comprehensive insights into its carcinogenic actions, highlighting its potential as both a prognostic indicator and a target for anti-cancer therapy. This integrative approach enhances our understanding of ACTL6A's role in cancer pathogenesis and treatment.

Targeting VPS72 inhibits ACTL6A/MYC axis activity in HCC progression.

HCC is a highly heterogeneous disease that is caused largely by genomic copy number variations. Herein, the mechanistic and therapeutically targeted role of vacuolar protein sorting 72 homologue (VPS72), a novel copy number variation cis-driven gained gene identified by genome-wide copy number variation and transcriptome analyses in HCC, is not well understood. First, overexpression of VPS72 enhanced the initiation and progression of HCC in vitro and in vivo . Mechanistically, VPS72 interacted with the oncoproteins MYC and actin-like 6A (ACTL6A) and promoted the formation of the ACTL6A/MYC complex. Furthermore, ACTL6A regulated VPS72 protein stability by weakening the interaction between tripartite motif containing 21 (TRIM21) and VPS72. Thus, the interaction between VPS72 and ACTL6A enhanced the affinity of MYC for its target gene promoters and promoted their transcription, thereby contributing to HCC progression, which was inhibited by adeno-associated virus serotype 8 (AAV8)-mediated short hairpin RNA (shRNA) against VPS72. This study reveals the molecular mechanism of ACTL6A/VPS72/MYC in HCC, providing a theoretical basis and therapeutic target for this malignancy.

ACTL6A deficiency induces apoptosis through impairing DNA replication and inhibiting the ATR-Chk1 signaling in glioblastoma cells

Actin-like 6A (ACTL6A) is a core subunit of the SWI/SNF chromatin remodeling complex and is highly expressed in several types of human cancers including glioblastoma. Recent studies verified that ACTL6A regulates the proliferation, differentiation, and migration of cancer cells. In this study, we identified ACTL6A as an important regulator of DNA replication. ACTL6A knockdown could impair the DNA replication initiation in glioblastoma cells. The regulation of DNA replication by ACTL6A was mediated through regulating the expression of the CDC45-MCM-GINS (CMG) complex genes. Further investigation revealed that ACTL6A transcriptionally regulates MCM5 expression. Furthermore, ACTL6A knockdown induced DNA damage and diminished the activity of the ATR-Chk1 pathway, which ultimately led glioblastoma cells to apoptosis and death. Taken together, our findings highlight the critical role of ACTL6A in DNA replication and ATR-Chk1 pathway, and reveal a potential target for therapeutic intervention in glioblastoma.

Upregulated Expression of Actin-Like 6A is a Risk Factor Affecting the Prognosis of Pancreatic Cancer.

PurposeActin-like 6A (ACTL6A), a regulatory subunit of the ATP-dependent chromatin-remodeling complex SWI/SNF, acts as an oncogenic factor. This study is aimed at evaluating the correlation between ACTL6A expression and clinicopathological parameters in pancreatic cancer (PC) patients.MethodsThe differences of Actl6a mRNA expression between PC tissues and normal pancreatic tissues were analyzed in public databases, and ACTL6A expression was then determined and confirmed in 60 paired tissue specimens using immunohistochemistry staining. The association analysis between ACTL6A expression and the clinicopathological characteristics was analyzed, as well as Kaplan–Meier survival analysis. Univariate and multivariate Cox analyses were performed to identify the prognostic factors in the overall survival (OS) of patients with PC.ResultsThe mRNA expression of Actl6a showed significantly higher in PC compared to normal controls (p < 0.05) from public databases. The score of immunohistochemistry staining further confirmed that ACTL6A expression was significantly upregulated in PC tissues (p < 0.001) through immunohistochemistry staining. High ACTL6A expression was associated with lymphovascular space invasion of PC. Kaplan–Meier analysis revealed that the high expression of ACTL6A was markedly associated with poor OS. Moreover, univariate and multivariate analysis demonstrated that ACTL6A acted as an independent risk factor for PC prognosis.ConclusionACTL6A is upregulated in PC and acts as a risk factor for poor prognosis in patients with PC, and therefore clinicians could around it design preventive measures and individualized treatment to improve mortality in patients with PC.

Increased ACTL6A occupancy within mSWI/SNF chromatin remodelers drives human squamous cell carcinoma

Mammalian SWI/SNF (BAF) chromatin remodelers play dosage-sensitive roles in many human malignancies and neurologic disorders. The gene encoding the BAF subunit actin-like 6a (ACTL6A) is amplified early in the development of many squamous cell carcinomas (SCCs), but its oncogenic role remains unclear. Here we demonstrate that ACTL6A overexpression leads to its stoichiometric assembly into BAF complexes and drives their interaction and engagement with specific regulatory regions in the genome. In normal epithelial cells, ACTL6A was substoichiometric to other BAF subunits. However, increased ACTL6A levels by ectopic expression or in SCC cells led to near saturation of ACTL6A within BAF complexes. Increased ACTL6A occupancy enhanced polycomb opposition genome-wide to activate SCC genes and facilitated the co-dependent loading of BAF and TEAD-YAP complexes on chromatin. Both mechanisms appeared to be critical and function as a molecular AND gate for SCC initiation and maintenance, thereby explaining the specificity of the role of ACTL6A amplification in SCCs.

ACTL6A promotes repair of cisplatin-induced DNA damage, a new mechanism of platinum resistance in cancer

Cisplatin is a mainstay of systemic therapy for a variety of cancers, such as lung cancer, head and neck cancer, and ovarian cancer. However, resistance to cisplatin represents one of the most significant barriers for patient outcome improvement. Actin-like 6A (ACTL6A) is a component of several chromatin remodeling complexes, including SWI/SNF, NuA4/TIP60 histone acetylase, and INO80. Amplification of ACTL6A gene is often seen in lung squamous cell carcinoma, ovarian cancer, and esophageal cancer, but its significance remains to be fully determined. Here we identify ACTL6A overexpression as a novel cause for platinum resistance. High levels of ACTL6A are associated with chemoresistance in several types of human cancer. We show that overexpression of ACTL6A leads to increased repair of cisplatin-DNA adducts and resistance to cisplatin treatment. In contrast, depletion of ACTL6A inhibits the repair of cisplatin-induced DNA lesions, and increases cisplatin sensitivity in cisplatin-resistant ovarian cancer cells. The regulation of repair by ACTL6A is mediated through the SWI/SNF chromatin remodeling complex. Treatment with a histone deacetylase inhibitor can reverse the effect of ACTL6A overexpression on the repair of cisplatin-induced DNA damage and render cancer cells more sensitive to cisplatin treatment in a xenograft mouse model. Taken together, our study uncovers a novel role for ACTL6A in platinum resistance, and provides evidence supporting the feasibility of using HDAC inhibitors for platinum resistant tumors.

ACTL6A knockdown inhibits cell migration by suppressing the AKT signaling pathway and enhances the sensitivity of glioma cells to temozolomide.

Molecular-targeted therapy has had a significant impact on glioma. Notably, actin-like 6A (ACTL6A) has been indicated to be essential for embryonic development and tumor progression. However, the role of ACTL6A in glioma remains unclear. The present study aimed to investigate the effects of ACTL6A on glioma cell migration and sensitivity to temozolomide (TMZ). The expression levels of ACTL6A were analyzed in patients with glioma, and survival curves were created using data from The Cancer Genome Atlas. U251 and T98G cells were transfected with short hairpin (sh)RNA for use in loss-of-function experiments to investigate the biological function and molecular mechanisms of ACTL6A. Furthermore, an MTT assay was used to assess the effect of ACTL6A on the sensitivity of glioma cells to TMZ. The results demonstrated that ACTL6A was expressed at higher levels in glioma tissues compared with normal brain tissues. Furthermore, high expression of ACTL6A was associated with a poor prognosis. The knockdown of ACTL6A significantly inhibited the migration phenotype in glioma cells and significantly decreased the levels of phosphorylated AKT in glioma cells. The AKT signaling activator SC79 partly attenuated the inhibitory effects of ACTL6A shRNA on glioma cell migration. Additionally, the knockdown of ACTL6A enhanced the sensitivity of glioma cells to TMZ. In conclusion, these results suggest that ACTL6A knockdown inhibited the migration of human glioma cells, at least in part through inactivation of the AKT signaling pathway, and increased the sensitivity of glioma cells to TMZ. Therefore, ACTL6A may be a potential therapeutic target for glioma.

Actin-like 6A enhances the proliferative and invasive capacities of laryngeal squamous cell carcinoma by potentiating the activation of YAP signaling.

Overexpression of Actin-like 6A (ACTL6A) has been observed in a wide spectrum of tumors and exerts an outstanding oncogenic function throughout cancer progression. However, the detailed relevance of ACTL6A for laryngeal squamous cell carcinoma (LSCC) is not fully understood. In this work, we aimed to elucidate the precise role of ACTL6A in LSCC. Here, we show that ACTL6A expression was significantly upregulated in LSCC versus normal tissues. In vitro functional assays demonstrated that silencing of ACTL6A significantly diminished the capacity of LSCC cells to proliferate and invade, whilst up-regulation of ACTL6A drove proliferation and invasion in LSCC cells. Further investigation revealed that knockdown of ACTL6A repressed the activation of Yes-associated protein (YAP)-mediated signaling in LSCC cells, while reactivation of YAP markedly reversed ACTL6A-silencing-mediated inhibition of proliferation and invasion in LSCC cells. Moreover, suppression of YAP markedly diminished ACTL6A-overexpression-induced promotion of tumor formation in LSCC. In addition, ACTL6A silencing diminished the tumorigenicity of LSCC cells in vivo. To summarize, our work indicates that ACTL6A may enhance LSCC progression via potentiating the activation of YAP signaling. Thus, ACTL6A may be an attractive anticancer target for the treatment of LSCC.

Enhanced SMARCD1, a subunit of the SWI/SNF complex, promotes liver cancer growth through the mTOR pathway.

The chromatin remodeling complex SWI/SNF regulates the accessibility of target genes to transcription factors and plays a critical role in the tumorigenesis of hepatocellular carcinoma (HCC). The SWI/SNF complex is assembled from approximately 15 subunits, and most of these subunits have distinct roles and are often aberrantly expressed in HCC. A comprehensive exploration of the expression and clinical significance of these subunits would be of great value. In the present study, we obtained the gene expression profile of each SWI/SNF subunit and the corresponding clinical information from The Cancer Genome Atlas (TCGA). We found that 14 out of the 15 SWI/SNF subunits were significantly increased in HCC tissues compared with paired normal liver tissues, and 11 subunits were significantly associated with overall survival (OS). We identified a four-gene prognostic signature including actin-like 6A (ACTL6A), AT-rich interaction domain 1A (ARID1A), SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily C member 1 (SMARCC1) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily D, member 1 (SMARCD1) that could effectively predict OS in HCC patients. Among the genes, SMARCD1 has the most prognostic value. We further conducted in vitro and in vivo experiments and revealed that SMARCD1 promotes liver cancer growth by activating the mTOR signaling pathway. In conclusion, our study has revealed that the expression of SWI/SNF complex subunits, especially SMARCD1, is highly associated with HCC development and acts as a promising prognostic predictor.

ACTL6A to drive gastric cancer progression through induction of glutathione synthesis.

e16521 Background: Actin-like 6A (ACTL6A), an actin-like protein, is a member of ATP-dependent SWI/SNF like BAF chromatin remodeling complexes. Previous reports revealed that ACTL6A was involved in varying cellular processes including chromatin remodeling, transcriptional regulation, vesicular transport, and nuclear migration. Nevertheless, its role and mechanism in Gastric Cancer (GC), the second leading causes of cancer-related death worldwide, has not been reported. To explore it, we found that ACTL6A inhibits ferroptosis of GC cells via regulating glutathione (GSH) metabolism. Ferroptosis is a regulated form of cell death driven by accumulation of lipid-based reactive oxygen species (ROS). Methods: GC cell line snu638 was used for studies. Firstly, silencing ACTL6A in snu638 with shRNA, cell proliferation was measured by counting cell confluence in incucyte. Overlapping the Gene Set Enrichment Analysis (GSEA) results of RNA-sequencing and two databases, we found that ACTL6A is positively correlated with GSH metabolism, which can be validated by real time-PCR. Next, cells were treated with ferrostatin-1 (fer-1), a ferroptosis inhibitor, to check if ACTL6A can inhibit ferroptosis. Finally, 13C-glucose and 13C-glutamine were used for tracing the metabolites in snu638, which were measured by LC-MS system. Results: Suppression of ACTL6A significantly inhibits GC cell growth. In our RNA-sequence results, ACTL6A is positively correlated with GSH metabolism, which is also enrich in two GC databases. ROS level was increased after ACTL6A knockdown. Since ROS plays an important role in ferroptosis, we found that fer-1 can rescue cell death caused by suppression of ACTL6A. When tracing with 13C-glucose, total GSH and 13C incorporation from 13C-glucose in the m+2 and m+4 isotopomer of GSH is reduced when ACTL6A is depleted, while total contribution of U-13C glucose to serine, glycine and glutamate have no significant changes. When tracing with 13C-glutamine, m+5 fractional contributions of 13C-glutamine to γ-glutamyl-cysteine and GSH are decreased when silencing ACTL6A. These results reveal that ACTL6A promotes de novo GSH synthesis. Conclusions: ACTL6A acts as an oncogene in GC via regulating GSH metabolism, and ferroptosis is inhibited for increasing GSH by ACTL6A, which highlights the importance of ACTL6A in GC metabolism and tumorigenesis. Therefore, ACTL6A could be a potential diagnosis marker or target gene of chemotherapy for GC.

MiR-216a-3p suppresses the proliferation and invasion of cervical cancer through downregulation of ACTL6A-mediated YAP signaling.

The tumor-suppressive role of microRNA-216a-3p (miR-216a-3p) has been evidenced in multiple tumors. Yet, the relevance of miR-216a-3p in cervical cancer remains undermined. The current study was designed to determine the expression and potential function of miR-216a-3p in cervical cancer. Expression of miR-216a-3p was markedly decreased in cervical cancer and functional assays revealed an inhibitory effect of miR-216a-3p on the proliferation, colony formation, and invasion of cervical cancer. Actin-like 6A (ACTL6A) was identified as a target gene of miR-216a-3p. Elevated ACTL6A expression was detected in cervical cancer, and ACTL6A inhibition exhibited a tumor-suppressive effect. ACTL6A inhibition increased yes-associated protein (YAP) phosphorylation and downregulated YAP-mediated transcriptional activity. ACTL6A restoration or YAP reactivation partially abrogated the miR-216a-3p-mediated antitumor effect in cervical cancer cells. Taken together, these data demonstrate that miR-216a-3p acts as a potential tumor-suppressive miRNA in cervical cancer, which exerts its function through inhibition of YAP signaling via targeting ACTL6A.

ACTL6A is a novel oncogene and prognostic biomarker for prostate cancer

Abstract ACTL6A (Actin-like 6A protein) is a member of ATP-dependent SWI/SNF-like BAF chromatin remodeling complexes encoding a family of actin-related proteins. Using 3D culture and Micro-Western Array analysis targeting for epigenetic regulatory proteins, we discovered that ACTL6A plays essential role in regulation of the prostate acinar morphogenesis, a differentiation procedure. Expression level of ACTL6A protein decreases dramatically during prostate acinar morphogenesis, suggesting that ACTL6A is a potential oncogene in prostate cancer (PCa). We analyzed Oncomine online database and found that ACTL6A is higher in prostate cancer vs. adjacent normal prostate tissues, while ACTL6A protein level is even higher in metastatic PCa. High ACTL6A gene expression level in prostate tumors correlates to worse PCa patient survival outcome. We knocked down ACTL6A in PC-3 PCa cells, and the reduction of ACTL6A suppressed proliferation, migration, and invasion of PC-3 cells. Knockdown of ACTL6A also reduced population of CD44+ and ALDH enzyme activity-positive PCa cells, which represents the population of cancer stem cell (CSC) in PCa. Decrease of ACTL6A reduced expression of a few oncogenic long non-coding RNA, including HIFCAR, MALAT1, and PCAT-1. Seahorse mito-stress and glycol-stress analysis revealed that knockdown of ACTL6A suppressed OCR and ECAR of mitochondria in PCa cells. ACTL6A knockdown up-regulates expression of glycolysis-related genes, suggesting that ACTL6A regulate cancer metabolism. Our study suggested that ACTL6A regulates expression and activity of YAP and c-Myc, which in turn regulates stemness factors Nanog and Sox2, thus enhances the cancer stemness of PCa cells. ACTL6A also regulates mitochondrial function and metabolic genes PKM2, LDHA, GLS1, partially through c-Myc, therefore ACTL6A causes metabolism rewiring in PCa. All these regulations contribute to the metastasis of PCa. In conclusion, ACTL6A is a novel oncogene and prognostic biomarker for PCa.

Abstract 5178: Genomic and transcriptomic alterations of chromatin factors in head and neck cancer

Abstract Chromatin factors play central roles in the transcriptional regulation and maintenance of genomic stability and have been implicated in cancer initiation and progression in multiple cancer types. No study has systematically investigated the genomic and expression alterations of chromatin factors in head and neck squamous cell carcinoma (HNSCC). To this purpose, we utilized the molecular profiles from over 510 HNSCCs in the Cancer Genome Atlas (TCGA), and thoroughly characterized the mutational, copy number and transcriptional alterations of 457 chromatin factors and histones. Over 75% of all HNSCC samples have genomic alterations in protein methyltransferases and protein demethylases. Protein lysine methyltransferases MLL2 and NSD1 are the most frequently mutated chromatin factors in this disease. Actin Like 6A (ACTL6A), a component of the SWI/SNF chromatin remodeling complex, SUMO specific peptidase 5 (SENP5) and Nuclear receptor binding SET domain protein 3 (NSD3) are the most frequently copy-number amplified and overexpressed chromatin factors. Interestingly, hierarchical clustering of gene expression of a set of chromatin factors identified a molecular subtype with significantly better overall survival (OS), regardless of HPV-status, stage and NSD1 mutation status, a factor recently reported to render better OS in HNSCC. Systematic characterization of the deregulation of chromatin factors may elucidate novel epigenetic mechanisms and provide novel targets for cancer therapy in HNSCC. Supported by NIDCD intramural projects ZIA-DC-000016, 73 and 74. Note: This abstract was not presented at the meeting. Citation Format: Hui Cheng, Riyue Bao, Carter Van Waes, Vassiliki Saloura. Genomic and transcriptomic alterations of chromatin factors in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5178.

ACTL6A interacts with p53 in acute promyelocytic leukemia cell lines to affect differentiation via the Sox2/Notch1 signaling pathway

Actin-like 6A (ACTL6A), a component of BAF chromatin remodeling complexes, is important for cell differentiation. Nevertheless, its role and mechanism in acute promyelocytic leukemia (APL) has not been reported. To identify the genes that may participate in the development of APL, we analyzed data from an APL cDNA microarray (GSE12662) in the NCBI database, and found that ACTL6A was up-regulated in APL patients. Subsequently, we investigated the function and mechanisms of ACTL6A in myeloid cell development. The expression of ACTL6A was gradually decreased during granulocytic differentiation in all-trans retinoic acid-treated NB4 and HL-60 cells, and phorbol myristate acetate-treated HL-60 cells. We also found that knockdown of ACTL6A promoted differentiation in NB4 and HL-60 cells, and decreased the levels of Sox2 and Notch1. Mechanistically, ACTL6A interacted with and was co-localized with Sox2 and p53. Meanwhile, CBL0137, an activator of p53, decreased the expression of ACTL6A and promoted differentiation in NB4 and HL-60 cells. These findings suggest that the inhibition of ACTL6A promotes differentiation via the Sox2 and Notch1 signaling pathways. Furthermore, the differentiation promoted by inhibiting ACTL6A could be regulated by p53 via its physical interaction with ACTL6A.

ACTL6A expression promotes invasion, metastasis and epithelial mesenchymal transition of colon cancer

BackgroundMetastasis is the main cause of death in patients with advanced stage colon cancer. Epithelial mesenchymal transition (EMT) plays an important role in invasion and metastasis. Actin-like 6A (ACTL6A) is vital for embryogenesis and differentiation and is also critical for metastasis and EMT in hepatocellular carcinoma, as observed in our previous study. In the present study, we further explored the role of ACTL6A in colon cancer metastasis.MethodsACTL6A expression levels were analyzed in normal colon, colon adenoma and colon cancer specimens using public databases and tissue samples. ACTL6A expression and its association with clinicopathologic features of colon cancer patients were also analyzed. ACTL6A-overexpression and ACTL6A-knockdown colon cancer cells were used to perform cytological experiments to explore the potential biological function of ACTL6A in metastasis and EMT in colon cancer.ResultsThe data from both the Gene Expression Omnibus (GEO) and Oncomine databases showed that ACTL6A expression levels in colon adenoma and cancer were higher than those in normal colon samples. The ACTL6A expression level in fresh colon cancer specimens was also higher than that in the corresponding adjacent normal colon specimens. Patients with high ACTL6A expression directly correlated with advanced pT status, distant metastasis, poor differentiation and microvascular/perineural invasion. ACTL6A overexpression promoted migration and invasion of colon cancer cells, whereas ACTL6A knockdown exhibited the opposite effect in vitro. Moreover, we demonstrated that ACTL6A promoted EMT in colon cancer cells in vitro.ConclusionsOur findings indicate that ACTL6A exhibits pro-tumor function and acts as an EMT activator in colon cancer. ACTL6A may serve as a potential therapeutic target for colon cancer.

Actin like-6A promotes glioma progression through stabilization of transcriptional regulators YAP/TAZ

Increased Actin-like 6A (ACTL6A) expression has been implicated in the development of diverse cancers and recently associated with the Hippo signaling pathway, which is known to regulate biological properties, including proliferation, tissue regeneration, stem cell biology, as well as tumorigenesis. Here we first show that ACTL6A is upregulated in human gliomas and its expression is associated with glioma patient survival. ACTL6A promotes malignant behaviors of glioma cells in vitro and in orthotopic xenograft model. In co-immunoprecipitation assays, we discover that ACTL6A physically associated with YAP/TAZ and furthermore disrupts the interaction between YAP and β-TrCP E3 ubiquitin ligase, which promotes YAP protein degradation. Moreover, effects of ACTL6A on glioma cells proliferation, migration, and invasion could be mediated by YAP/TAZ. These data indicate that ACTL6A may contribute to cancer progression by stabilizing YAP/TAZ and therefore provide a novel therapeutic target for the treatment of human gliomas.