YAP1 maintains active chromatin state in head and neck squamous cell carcinomas that promotes tumorigenesis through cooperation with BRD4

Nana Chen; Gabriel Golczer; Subhoshree Ghose; Brian Lin; Adam Langenbucher; Jason Webb; Haymanti Bhanot; Nicholas B. Abt; Derrick Lin; Mark Varvares; Martin Sattler; Ann Marie Egloff; Richard Joh; Ravindra Uppaluri; Kevin S. Emerick; Michael S. Lawrence; Srinivas Vinod Saladi

Cell Reports (Jun 2022)

YAP1 maintains active chromatin state in head and neck squamous cell carcinomas that promotes tumorigenesis through cooperation with BRD4

Nana Chen,
Gabriel Golczer,
Subhoshree Ghose,
Brian Lin,
Adam Langenbucher,
Jason Webb,
Haymanti Bhanot,
Nicholas B. Abt,
Derrick Lin,
Mark Varvares,
Martin Sattler,
Ann Marie Egloff,
Richard Joh,
Ravindra Uppaluri,
Kevin S. Emerick,
Michael S. Lawrence,
Srinivas Vinod Saladi

Affiliations

Nana Chen: Department of Otolaryngology Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Head and Neck Lab, 20 Staniford Street 2W, Boston, MA 02114, USA
Gabriel Golczer: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Subhoshree Ghose: Department of Otolaryngology Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Head and Neck Lab, 20 Staniford Street 2W, Boston, MA 02114, USA
Brian Lin: Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Adam Langenbucher: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Jason Webb: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02114, USA
Haymanti Bhanot: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA
Nicholas B. Abt: Department of Otolaryngology Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Head and Neck Lab, 20 Staniford Street 2W, Boston, MA 02114, USA
Derrick Lin: Department of Otolaryngology Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Head and Neck Lab, 20 Staniford Street 2W, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Mark Varvares: Department of Otolaryngology Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Head and Neck Lab, 20 Staniford Street 2W, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Martin Sattler: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA
Ann Marie Egloff: Department of Surgery, Brigham and Women’s Hospital, Boston, MA 02115, USA
Richard Joh: Department of Physics, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23284, USA
Ravindra Uppaluri: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Brigham and Women’s Hospital, Boston, MA 02115, USA
Kevin S. Emerick: Department of Otolaryngology Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Head and Neck Lab, 20 Staniford Street 2W, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Michael S. Lawrence: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Srinivas Vinod Saladi: Department of Otolaryngology Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Head and Neck Lab, 20 Staniford Street 2W, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Corresponding author

Journal volume & issue: Vol. 39, no. 11
p. 110970

Abstract

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Summary: Analysis of The Cancer Genome Atlas and other published data of head and neck squamous cell carcinoma (HNSCC) reveals somatic alterations of the Hippo-YAP pathway in approximately 50% of HNSCC. Better strategies to target the YAP1 transcriptional complex are sought. Here, we show that FAT1, an upstream inhibitor of YAP1, is mutated either by missense or by truncating mutation in 29% of HNSCC. Comprehensive proteomic and drug-screening studies across pan-cancer models confirm that FAT1-mutant HNSCC exhibits selective and higher sensitivity to BRD4 inhibition by JQ1. Epigenomic analysis reveals an active chromatin state in FAT1-mutant HNSCC cells that is driven by the YAP/TAZ transcriptional complex through recruitment of BRD4 to deposit active histone marks, thereby maintaining an oncogenic transcriptional state. This study reveals a detailed cooperative mechanism between YAP1 and BRD4 in HNSCC and suggests a specific therapeutic opportunity for the treatment of this subset of head and neck cancer patients.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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