Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Saladi SV

PROVIDER: S-EPMC5225026 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Saladi Srinivas Vinod SV Ross Kenneth K Karaayvaz Mihriban M Tata Purushothama R PR Mou Hongmei H Rajagopal Jayaraj J Ramaswamy Sridhar S Ellisen Leif W LW

Cancer cell 20161229 1

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 ...[more]

PMID: 28041841

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Project description:BackgroundACTL6A, 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 methodsWe 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.ResultsACTL6A 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.ConclusionACTL6A 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.

Dataset Information

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

Publications

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

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