Cistrome analysis of YY1 uncovers a regulatory axis of YY1:BRD2/4-PFKP during tumorigenesis of advanced prostate cancer.

Journal Article (Journal Article)

Castration-resistant prostate cancer (CRPC) is a terminal disease and the molecular underpinnings of CRPC development need to be better understood in order to improve its treatment. Here, we report that a transcription factor Yin Yang 1 (YY1) is significantly overexpressed during prostate cancer progression. Functional and cistrome studies of YY1 uncover its roles in promoting prostate oncogenesis in vitro and in vivo, as well as sustaining tumor metabolism including the Warburg effect and mitochondria respiration. Additionally, our integrated genomics and interactome profiling in prostate tumor show that YY1 and bromodomain-containing proteins (BRD2/4) co-occupy a majority of gene-regulatory elements, coactivating downstream targets. Via gene loss-of-function and rescue studies and mutagenesis of YY1-bound cis-elements, we unveil an oncogenic pathway in which YY1 directly binds and activates PFKP, a gene encoding the rate-limiting enzyme for glycolysis, significantly contributing to the YY1-enforced Warburg effect and malignant growth. Altogether, this study supports a master regulator role for YY1 in prostate tumorigenesis and reveals a YY1:BRD2/4-PFKP axis operating in advanced prostate cancer with implications for therapy.

Full Text

Duke Authors

Cited Authors

  • Xu, C; Tsai, Y-H; Galbo, PM; Gong, W; Storey, AJ; Xu, Y; Byrum, SD; Xu, L; Whang, YE; Parker, JS; Mackintosh, SG; Edmondson, RD; Tackett, AJ; Huang, J; Zheng, D; Earp, HS; Wang, GG; Cai, L

Published Date

  • May 21, 2021

Published In

Volume / Issue

  • 49 / 9

Start / End Page

  • 4971 - 4988

PubMed ID

  • 33849067

Pubmed Central ID

  • PMC8136773

Electronic International Standard Serial Number (EISSN)

  • 1362-4962

Digital Object Identifier (DOI)

  • 10.1093/nar/gkab252

Language

  • eng

Conference Location

  • England