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

Srinivas Vinod Saladi; Kenneth Ross; Mihriban Karaayvaz; Purushothama R Tata; Hongmei Mou; Jayaraj Rajagopal; Sridhar Ramaswamy; Leif W Ellisen

doi:10.1016/j.ccell.2016.12.001

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

Cancer Cell. 2017 Jan 9;31(1):35-49. doi: 10.1016/j.ccell.2016.12.001. Epub 2016 Dec 29.

Authors

Srinivas Vinod Saladi¹, Kenneth Ross², Mihriban Karaayvaz¹, Purushothama R Tata³, Hongmei Mou³, Jayaraj Rajagopal⁴, Sridhar Ramaswamy⁵, Leif W Ellisen⁶

Affiliations

¹ Massachusetts General Hospital Cancer Center, GRJ-904, 55 Fruit Street, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
² Massachusetts General Hospital Cancer Center, GRJ-904, 55 Fruit Street, Boston, MA 02114, USA.
³ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Harvard Medical School, Boston, MA 02115, USA.
⁴ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Internal Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Harvard Medical School, Boston, MA 02115, USA.
⁵ Massachusetts General Hospital Cancer Center, GRJ-904, 55 Fruit Street, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02138, USA.
⁶ Massachusetts General Hospital Cancer Center, GRJ-904, 55 Fruit Street, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: lellisen@mgh.harvard.edu.

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.

Keywords: ACTL6A; HNSCC; SWI/SNF (BAF) complex; YAP1; chromatin remodeling; hippo pathway; p63; squamous cell carcinoma.

MeSH terms

Actins / physiology*
Adaptor Proteins, Signal Transducing / physiology*
Animals
Carcinoma, Squamous Cell / etiology*
Carcinoma, Squamous Cell / mortality
Cell Line, Tumor
Cell Proliferation
Chromosomal Proteins, Non-Histone / physiology*
DNA-Binding Proteins / physiology*
Head and Neck Neoplasms / etiology*
Head and Neck Neoplasms / mortality
Hippo Signaling Pathway
Humans
Intracellular Signaling Peptides and Proteins / physiology
Membrane Proteins / physiology*
Mice
Phosphoproteins / physiology*
Prognosis
Protein Serine-Threonine Kinases / physiology
Squamous Cell Carcinoma of Head and Neck
Transcription Factors
Transcriptome
YAP-Signaling Proteins

Substances

ACTL6A protein, human
Actins
Adaptor Proteins, Signal Transducing
CKAP4 protein, human
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Phosphoproteins
Transcription Factors
WWC1 protein, human
YAP-Signaling Proteins
YAP1 protein, human
Protein Serine-Threonine Kinases

Abstract

MeSH terms

Substances

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