BRD4 REGULATES TRANSCRIPTION FACTOR ∆Np63αTO DRIVE A CANCER STEM CELL PHENOTYPE IN SQUAMOUS CELL CARCINOMAS

Fisher, Matthew L, Balinth, Seamus, Hwangbo, Yon, Wu, Caizhi, Ballon, Carlos, Wilkinson, John E, Goldberg, Gary L, Mills, Alea A (October 2021) BRD4 REGULATES TRANSCRIPTION FACTOR ∆Np63αTO DRIVE A CANCER STEM CELL PHENOTYPE IN SQUAMOUS CELL CARCINOMAS. Cancer Research. canres.0707.2021-canres.0707.2021. ISSN 0008-5472

Abstract

Bromodomain containing protein 4 (BRD4) plays a critical role in controlling the expression of genes involved in development and cancer. Inactivation of BRD4 inhibits cancer growth, making it a promising anticancer drug target. The cancer stem cell population is a key driver of recurrence and metastasis in cancer patients. Here we show that cancer stem-like cells can be enriched from squamous cell carcinomas, and that these cells display an aggressive phenotype with enhanced stem cell marker expression, migration, invasion, and tumor growth. BRD4 was highly elevated in this aggressive subpopulation of cells, and its function is critical for these cancer stem cell-like properties. Moreover, BRD4 regulated ∆Np63α, a key transcription factor that is essential for epithelial stem cell function that is often overexpressed in cancers. BRD4 regulated an EZH2/STAT3 complex that led to increased ∆Np63α-mediated transcription. Targeting BRD4 in human squamous cell carcinoma reduces ∆Np63α, leading to inhibition of spheroid formation, migration, invasion and tumor growth. These studies identify a novel BRD4-regulated signaling network in a subpopulation of cancer stem-like cells elucidating a possible avenue for effective therapeutic intervention.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > BET bromodomain coactivator protein bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > BET bromodomain coactivator protein > Brd4 organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > drugs and therapies organism description > animal > mammal diseases & disorders > cancer > metastasis organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:	Fisher, Matthew L Balinth, Seamus Wu, Caizhi Mills, Alea A. Ballon, Carlos
Communities:	CSHL labs > Mills lab CSHL Cancer Center Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	25 October 2021
Date Deposited:	27 Oct 2021 13:50
Last Modified:	13 Feb 2024 16:46
PMCID:	PMC8692924
URI:	https://repository.cshl.edu/id/eprint/40398

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