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.

High expression of ACTL6A leads to poor prognosis of oral squamous cell carcinoma patients through promoting malignant progression.

OBJECTIVE: The aim was to research ACTL6A's role in oral squamous cell carcinoma (OSCC). METHODS: OSCC and normal samples were obtained from patients and public databases. GSEA was performed. CIBERSORT was utilized to analyze immune landscape. Kaplan-Meier survival analysis and multivariate Cox regression analysis were conducted. After knocking down ACTL6A, we performed MTT assay, transwell assays, and flow cytometry to detect the impact of knockdown. RESULTS: ACTL6A expressed higher in OSCC samples than normal samples. The CNV and mutation rate of TP53 was higher in ACTL6A high-expression group. TFs E2F7 and TP63 and miRNA hsa-mir-381 were significantly related to ACTL6A. ACTL6A could influence immune microenvironment of OSCC. Knockdown of ACTL6A inhibited OSCC cells' proliferation, migration, and invasion. ACTL6A was able to predict OSCC prognosis independently. CONCLUSION: ACTL6A expressed higher in OSCC than normal samples and it could be used as an independent prognostic marker in OSCC patients.

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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Sulforaphane suppresses cell proliferation and induces apoptosis in glioma via the ACTL6A/PGK1 axis.

This study aimed to examine the expression and biological functions of ACTL6A in glioma cells (U251), the effects of sulforaphane on the growth of U251 cells and the involvement of the ACTL6A/PGK1 pathway in those effects. The U251 cell line was transfected with ACTL6A over-expression plasmids to upregulate the protein, or with ACTL6A inhibitor to underexpress it, then treated with different concentrations of sulforaphane. Cell viability, proliferation, and apoptosis were assessed using standard assays, and levels of mRNAs encoding ACTL6A, PGK1, cyclin D1, Myc, Bax or Bcl-2 were measured using quantitative real-time polymerase chain reaction (qRT-PCR). ACTL6A and PGK1 were expressed at higher levels in glioma cell lines than in normal HEB cells. ACTL6A overexpression upregulated PGK1, whereas ACTL6A inhibition had the opposite effect. ACTL6A overexpression induced proliferation, whereas its inhibition repressed proliferation, enhanced apoptosis, and halted the cell cycle. Moreover, sulforaphane suppressed the growth of U251 cells by inactivating the ACTL6A/PGK1 axis. ACTL6A acts via PGK1 to play a critical role in glioma cell survival and proliferation, and sulforaphane targets it to inhibit glioma.

Involvement of transcribed lncRNA uc.291 in hyperproliferative skin disorders.

The uc.291 transcript controls keratinocytes differentiation by physical interaction with ACTL6A and subsequent induction of transcription of the genes belonging to the epidermal differentiation complex (EDC). Uc.291 is also implicated in the dedifferentiation phenotype seen in poorly differentiated cutaneous squamous cell carcinomas. Here, we would like to investigate the contribution of uc.291 to the unbalanced differentiation state of keratinocytes observed in hyperproliferative skin disorders, e. g., psoriasis. Psoriasis is a multifactorial inflammatory disease, caused by alteration of keratinocytes homeostasis. The imbalanced differentiation state, triggered by the infiltration of immune cells, represents one of the events responsible for this pathology. In the present work, we explore the role of uc.291 and its interactor ACTL6A in psoriasis skin, using quantitative real-time PCR (RT-qPCR), immunohistochemistry and bioinformatic analysis of publicly available datasets. Our data suggest that the expression of the uc.291 and of EDC genes loricrin and filaggrin (LOR, FLG) is reduced in lesional skin compared to nonlesional skin of psoriatic patients; conversely, the mRNA and protein level of ACTL6A are up-regulated. Furthermore, we provide evidence that the expression of uc.291, FLG and LOR is reduced, while ACTL6A mRNA is up-regulated, in an in vitro psoriasis-like model obtained by treating differentiated keratinocytes with interleukin 22 (IL-22). Furthermore, analysis of a publicly available dataset of human epidermal keratinocytes treated with IL-22 (GSE7216) confirmed our in vitro results. Taken together, our data reveal a novel role of uc.291 and its functional axis with ACTL6A in psoriasis disorder and a proof of concept that biological inhibition of this molecular axis could have a potential pharmacological effect against psoriasis and, in general, in skin diseases with a suppressed differentiation programme.

Actin-like Protein 6A Expression Correlates with Cancer Stem Cell-like Features and Poor Prognosis in Ovarian Cancer.

Ovarian cancer has the highest mortality rate among gynecological cancers, often diagnosed at the late stage and lacking an effective targeted therapy. Although the study of malignant features of cancer, considered to be cancer stem cells (CSCs), is emerging, the aim of this study was to predict and explore the possible mechanism and clinical value of genetic markers in the development of ovarian cancer from a combined database with CSCs features. The common differentially expressed genes (DEGs) were selected in GSE185833 and GSE176246 datasets from the Gene Expression Omnibus (GEO). The GSE185833 dataset was created to reveal gene expression profiles of peritoneal metastasis tissues using single-cell sequencing, and the GSE176246 dataset was determined from gene expression profiles of chemotherapy-refractory ovarian cancer cell lines compared with ovarian cancer cell lines by RNA-seq analysis. By analyzing the correlation between common DEGs and prognosis of ovarian cancer and its possible pathways and functions were predicted by The Cancer Genome Atlas (TCGA) database. The expression levels of 11 genetic markers were significantly elevated in highly invasive and chemoresistant ovarian cancer. The expression of Actin-like protein 6A (ACTL6A) was found to be correlated with survival prognosis, and the total survival time of the patients with high expression of ACTL6A was shorter than those with low expression. Gene set enrichment analysis (GSEA) showed that ACTL6A positively enriched the gene set of 'Cell cycle' and ACTL6A negatively enriched the gene set of focal adhesion. CP724714, a human epidermal growth factor receptor 2 (HER2) inhibitor, could serve as a therapeutic option when ACTL6A levels are high in ovarian cancer cells. The high expression of ACTL6A is a poor prognostic factor in ovarian cancer and may serve as an effective biomarker for predicting treatment-refractory, metastasis, and prognosis of patients with ovarian cancer. The use of HER2 inhibitors is a promising therapeutic strategy against chemoresistant ovarian cancer.

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.

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.

Case Report: BAF-Opathies/SSRIDDs Due to a de novo ACTL6A Variant, Previously Considered to Be Heart-Hand Syndrome.

Purpose: This study aims to identify genetic lesions in patients with congenital heart disease (CHD) with or without other phenotypes. In this study, over 400 patients were recruited and several novel variants in known causative genes were identified. A Chinese patient clinically diagnosed with HHS (patent ductus arteriosus, persistent left superior vena cava, and congenital absence of left arm radius) was included in the study cohort. Methods: Targeted, whole exome, and Sanger sequencing were performed to identify genetic lesions. The effects of the variant on ACTL6A RNA and protein were assessed using bioinformatics analysis. Results: At the start of the study, no mutations in known and candidate causative genes associated with CHD were identified. Seven years later, we noticed craniofacial deformities and identified a de novo heterozygous deletion variant in ACTL6A (NM_004301, c.478_478delT; p.F160Lfs*9). Intellectual disability and short stature were identified by a follow-up visit 10 years later. This variant leads to frameshift sequences and a premature termination codon and may affect the features of proteins. According to the nonsense-mediated mRNA decay theory, this variant may induce the decay of ACTL6A mRNA in patients. Conclusion: Our study reported the first ACTL6A variant in a Chinese individual, providing further evidence that ACTL6A is involved in heart and upper limb skeletal and intellectual development, thereby expanding the spectrum of ACTL6A variants. Thus, mutation analysis of the ACTL6A gene should be considered in patients with BAF-opathies or heart-hand syndromes due to potential misdiagnosis. Craniofacial dysmorphisms and intellectual disability are key to distinguishing these two diseases clinically, and attention to developmental delay/intellectual disability and craniofacial deformities will contribute to the diagnosis of BAF-opathies.

Potential Role of SWI/SNF Complex Subunit Actin-Like Protein 6A in Cervical Cancer.

SWI/SNF complex subunit Actin-like protein 6A (ACTL6A) has been regarded as an oncogene, regulating the proliferation, migration and invasion of cancer cells. However, the expression pattern and biological role of ACTL6A in cervical cancer have not been reported. In this study, the mRNA expression and protein level of ACTL6A in cervical cancer samples were determined by public database and immunohistochemical (IHC) analysis. The effects of ACTL6A on cervical cancer cells were investigated via MTT, colony-formation assay, tumor xenografts and flow cytometry. Gene set enrichment analysis (GSEA) was used to explore the potential mechanism of ACTL6A in regulating tumorigenesis of cervical cancer. The results revealed that ACTL6A was markedly upregulated in cervical cancer tissues. Silencing ACTL6A expression resulted in decreased cervical cancer cell proliferation, colony formation and tumorigenesis in vitro and in vivo. Furthermore, we demonstrated that knockdown of ACTL6A induced cell cycle arrest at G1 phase, ACTL6A-mediated proliferation and cell cycle progression were c-Myc dependent. Our study provides the role of ACTL6A in cervical oncogenesis and reveals a potential target for therapeutic intervention in this cancer type.

ACTL6A promotes the growth in non-small cell lung cancer by regulating Hippo/Yap pathway.

Purpose: To delve into the related molecular mechanism of ACTL6A on non-small cell lung cancer (NSCLC) cell growth and apoptosis.Methods: Quantitative real-time polymerase chain reaction, immunohistochemical staining, and western blot assays were employed to examine ACTL6A mRNA and protein expression in four NSCLC cell line (NCI-H2170, LTEP-s, NCI-H1703, and PC-9) and normal lung cell line (BEAS-2B). CCK-8 cell viability assays and clone formation assay were applied to verify the cell proliferation of NCI-H2170 cell line after knockdown of ACTL6A. Flow cytometry assays were applied to check the role of ACTL6A in the apoptosis of NSCLC cells. The western blot assays were employed to examine the protein expression of WWC1, YAP, TAZ, and CYR61 in NCI-H2170 after knockdown of ACTL6A. Finally, xenograft tumor was taken out and checked the tumor volumes and weight. Immunohistochemical staining and western blot assays were employed to examine cell proliferation and apoptosis of NSCLC in vivo.Results: In this study, the results showed that the mRNA and protein expression level of ACTL6A was higher in four NSCLC cell line than normal lung cell line, respectively. Suppression of ACTL6A inhibited the growth and promoted apoptosis of NSCLC cells. Meanwhile, ACTL6A promotes tumor growth and inhibits apoptosis of NSCLC in vivo via Hippo/YAP signaling pathway.Conclusion: ACTL6A promotes the proliferation in NSCLC by regulating Hippo/YAP pathway.

Actin-like protein 6A/MYC/CDK2 axis confers high proliferative activity in triple-negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high proliferative activity. TNBC tumors exhibit elevated MYC expression and altered expression of MYC regulatory genes, which are associated with tumor progression and poor prognosis; however, the underlying mechanisms by which MYC retains its high expression and mediates TNBC tumorigenesis require further exploration. METHODS: ACTL6A regulation of MYC and its target gene, CDK2, was defined using Co-IP, mass spectrometry and ChIP assays. To study the role of ACTL6A in TNBC, we performed soft-agar, colony formation, flow cytometry and tumor formation in nude mice. CDK2 inhibitor and paclitaxel were used in testing combination therapy in vitro and in vivo. RESULTS: ACTL6A bound MYC to suppress glycogen synthase kinase 3 beta (GSK3ß)-induced phosphorylation on MYC T58, which inhibited ubiquitination of MYC and stabilized it. Moreover, ACTL6A promoted the recruitment of MYC and histone acetyltransferase KAT5 on CDK2 promoters, leading to hyperactivation of CDK2 transcription. ACTL6A overexpression promoted, while silencing ACTL6A suppressed cell proliferation and tumor growth in TNBC cells in vitro and in vivo, which was dependent on MYC signaling. Furthermore, co-therapy with paclitaxel and CDK2 inhibitor showed synergistic effects in tumor suppression. Notably, ACTL6A/MYC/CDK2 axis was specifically up-regulated in TNBC and high expression of ACTL6A was correlated to shorter survival in patients with TNBC. CONCLUSIONS: These findings reveal a novel mechanism by which ACTL6A prolongs the retention of MYC in TNBC and suggest that pharmacological targeting ACTL6A/MYC/CDK2 axis might have therapeutic potential in patients with TNBC.

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 Promotes the Proliferation of Esophageal Squamous Cell Carcinoma Cells and Correlates with Poor Clinical Outcomes.

BACKGROUND: ACTL6A, a regulatory subunit of ATP-dependent chromatin-remodeling complexes SWI/SNF, has been identified as a central oncogenic driver in many tumor types. MATERIALS AND METHODS: We used immunohistochemistry (IHC) to detect ACTL6A expression in esophageal squamous cell carcinoma (ESCC) tissues. Then, the effect of ACTL6A on proliferation and DNA synthesis was explored by using cell counting kit 8 (CCK8) and EdU retention assays. The potential oncogenic mechanism of ACTL6A in ESCC cells was also analyzed by flow cytometry and Western blotting. We further established an ESCC xenograft mouse model to validate the in vitro results. RESULTS: ACTL6A expression, localized in cancer cell nuclei, was markedly higher in ESCC tissues than in the corresponding noncancerous tissues (P<0.001) and was positively associated with tumor size, histological differentiation, T stage and tumor-node-metastasis (TNM) stage. Kaplan-Meier analysis revealed that high ACTL6A expression was significantly associated with poor overall survival (OS) (P = 0.008, HR= 2.562, 95% CI: 1.241-5.289), and decision curve analysis (DCA) demonstrated that ACTL6A could increase the clinical prognostic efficiency of the original clinical prediction model. Further in vitro experiments showed that ACTL6A knockdown led to inhibition of cell proliferation and DNA synthesis in ESCC cell lines, while overexpression of ACTL6A had the opposite effects. ACTL6A knockdown resulted in G1 phase arrest, with downregulation of cyclin D1, CDK2 and S6K1/pS6 pathway proteins and upregulation of p21 and p27, while overexpression of ACTL6A facilitated the entry of more cells into S phase with upregulated cyclin D1, CDK2 and S6K1/pS6 pathway proteins and downregulated p21 and p27. Finally, a xenograft mouse model of ESCC cells validated the results in vitro. CONCLUSION: ACTL6A expression may affect the proliferation and DNA synthesis of ESCC cells by facilitating ESCC cell cycle redistribution via the S6K1/pS6 pathway. Therefore, ACTL6A may potentially become an alternative therapeutic target for ESCC.

Involvement of transcribed lncRNA uc.291 and SWI/SNF complex in cutaneous squamous cell carcinoma.

While non-melanoma skin cancers (NMSCs) are the most common tumours in humans, only the sub-type cutaneous squamous cell carcinoma (cSCC), might become metastatic with high lethality. We have recently identified a regulatory pathway involving the lncRNA transcript uc.291 in controlling the expression of epidermal differentiation complex genes via the interaction with ACTL6A, a component of the chromatin remodelling complex SWI/SNF. Since transcribed ultra-conserved regions (T-UCRs) are expressed in normal tissues and are deregulated in tumorigenesis, here we hypothesize a potential role for dysregulation of this axis in cSCC, accounting for the de-differentiation process observed in aggressive poorly differentiated cutaneous carcinomas. We therefore analysed their expression patterns in human tumour biopsies at mRNA and protein levels. The results suggest that by altering chromatin accessibility of the epidermal differentiation complex genes, down-regulation of uc.291 and BRG1 expression contribute to the de-differentiation process seen in keratinocyte malignancy. This provides future direction for the identification of clinical biomarkers in cutaneous SCC. Analysis of publicly available data sets indicates that the above may also be a general feature for SCCs of different origins.

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.

Long non-coding RNA uc.291 controls epithelial differentiation by interfering with the ACTL6A/BAF complex.

The mechanisms that regulate the switch between epidermal progenitor state and differentiation are not fully understood. Recent findings indicate that the chromatin remodelling BAF complex (Brg1-associated factor complex or SWI/SNF complex) and the transcription factor p63 mutually recruit one another to open chromatin during epidermal differentiation. Here, we identify a long non-coding transcript that includes an ultraconserved element, uc.291, which physically interacts with ACTL6A and modulates chromatin remodelling to allow differentiation. Loss of uc.291 expression, both in primary keratinocytes and in three-dimensional skin equivalents, inhibits differentiation as indicated by epidermal differentiation complex genes down-regulation. ChIP experiments reveal that upon uc.291 depletion, ACTL6A is bound to the differentiation gene promoters and inhibits BAF complex targeting to induce terminal differentiation genes. In the presence of uc.291, the ACTL6A inhibitory effect is released, allowing chromatin changes to promote the expression of differentiation genes. Thus, uc.291 interacts with ACTL6A to modulate chromatin remodelling activity, allowing the transcription of late differentiation genes.

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

BACKGROUND: Metastasis 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. METHODS: ACTL6A 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. RESULTS: The 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. CONCLUSIONS: Our 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.

Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability.

Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to ß-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.

ACTL6A Is Co-Amplified with p63 in Squamous Cell Carcinoma to Drive YAP Activation, Regenerative Proliferation, and Poor Prognosis.

Loss-of-function mutations in SWI/SNF chromatin-remodeling subunit genes are observed in many cancers, but an oncogenic role for SWI/SNF is not well established. Here, we reveal that ACTL6A, encoding an SWI/SNF subunit linked to stem cell and progenitor cell function, is frequently co-amplified and highly expressed together with the p53 family member p63 in head and neck squamous cell carcinoma (HNSCC). ACTL6A and p63 physically interact, cooperatively controlling a transcriptional program that promotes proliferation and suppresses differentiation, in part through activation of the Hippo-YAP pathway via regulators including WWC1. Ectopic ACTL6A/p63 expression promotes tumorigenesis, while ACTL6A expression and YAP activation are highly correlated in primary HNSCC and predict poor patient survival. Thus, ACTL6A and p63 collaborate as oncogenic drivers in HNSCC.