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

doi:10.1016/j.celrep.2022.110970

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

Cell Rep. 2022 Jun 14;39(11):110970. doi: 10.1016/j.celrep.2022.110970.

Authors

Nana Chen¹, Gabriel Golczer², Subhoshree Ghose¹, Brian Lin³, Adam Langenbucher², Jason Webb⁴, Haymanti Bhanot⁵, Nicholas B Abt¹, Derrick Lin⁶, Mark Varvares⁶, Martin Sattler⁵, Ann Marie Egloff⁷, Richard Joh⁸, Ravindra Uppaluri⁹, Kevin S Emerick⁶, Michael S Lawrence¹⁰, Srinivas Vinod Saladi¹¹

Affiliations

¹ 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.
² Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
³ Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02114, USA.
⁵ 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.
⁶ 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.
⁷ Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁸ Department of Physics, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23284, USA.
⁹ 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.
¹⁰ Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹¹ 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. Electronic address: srinivasvinod_saladi@meei.harvard.edu.

PMID: 35705032
DOI: 10.1016/j.celrep.2022.110970

Abstract

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.

Keywords: ATAD2; BRD4; CP: Cancer; CP: Molecular biology; FAT1 mutation; HNSCC; JQ1; NRG1; OTX-015; PD-L1; YAP1; hippo pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinogenesis / genetics
Carcinogenesis / metabolism
Cell Cycle Proteins* / genetics
Cell Cycle Proteins* / metabolism
Cell Line, Tumor
Chromatin
Head and Neck Neoplasms* / genetics
Humans
Nuclear Proteins* / genetics
Proteomics
Squamous Cell Carcinoma of Head and Neck
Transcription Factors* / genetics
Transcription Factors* / metabolism
YAP-Signaling Proteins* / genetics
YAP-Signaling Proteins* / metabolism

Substances

BRD4 protein, human
Cell Cycle Proteins
Chromatin
Nuclear Proteins
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human