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

• Published in: Cancer cell Vol. 31; no. 1; pp. 35 - 49
• Main Authors: Saladi, Srinivas Vinod, Ross, Kenneth, Karaayvaz, Mihriban, Tata, Purushothama R., Mou, Hongmei, Rajagopal, Jayaraj, Ramaswamy, Sridhar, Ellisen, Leif W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.01.2017
• Subjects: Actins - physiology; ACTL6A; Adaptor Proteins, Signal Transducing - physiology; Animals; Carcinoma, Squamous Cell - etiology; Carcinoma, Squamous Cell - mortality; Cell Line, Tumor; Cell Proliferation; chromatin remodeling; Chromosomal Proteins, Non-Histone - physiology; DNA-Binding Proteins - physiology; Head and Neck Neoplasms - etiology; Head and Neck Neoplasms - mortality; hippo pathway; HNSCC; Humans; Intracellular Signaling Peptides and Proteins - physiology; Membrane Proteins - physiology; Mice; p63; Phosphoproteins - physiology; Prognosis; Protein-Serine-Threonine Kinases - physiology; squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; SWI/SNF (BAF) complex; Transcription Factors; Transcriptome; YAP1; YAP1; hippo pathway; HNSCC; ACTL6A; chromatin remodeling; SWI/SNF (BAF) complex; p63; squamous cell carcinoma
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2016.12.001

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. [Display omitted] •ACTL6A is co-amplified, co-expressed, and physically associated with p63 in HNSCC•ACTL6A/p63-mediated transcription drives undifferentiated regenerative proliferation•An ACTL6A/p63 complex suppresses WWC1 to activate YAP and promote tumorigenesis•ACTL6A and an activated YAP pathway confer poor prognosis in primary HNSCC Saladi et al. show that ACTL6A, which encodes an SWI/SNF subunit, is frequently amplified and highly expressed together with TP63 in head and neck squamous cell carcinoma (HNSCC). ACTL6A and p63 coordinately regulate key genes, including WWC1, to dictate oncogenic YAP activity and patient outcomes in HNSCC.