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

Nucleic Acids Res. 2021 May 21;49(9):4971-4988. doi: 10.1093/nar/gkab252.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic*
  • Glycolysis
  • HEK293 Cells
  • Humans
  • Male
  • Mice, SCID
  • Phosphofructokinase-1, Type C / genetics*
  • Phosphofructokinase-1, Type C / physiology
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • YY1 Transcription Factor / genetics
  • YY1 Transcription Factor / metabolism*
  • YY1 Transcription Factor / physiology


  • BRD2 protein, human
  • BRD4 protein, human
  • Cell Cycle Proteins
  • Transcription Factors
  • YY1 Transcription Factor
  • YY1 protein, human
  • Phosphofructokinase-1, Type C
  • PFKP protein, human