The Role of YY1 in Castration-Resistant Prostate Cancer

PROJECT SUMMARY/ABSTRACT
Standard treatment of prostate cancer with current agents fails due to development of therapy resistance and
castration-resistant prostate cancer (CRPC), a terminal disease. CRPC differs from early-staged prostate
cancer in its increased reliance on glycolysis (the Warburg effect) as well as emergence of therapy resistance
due to the androgen receptor (AR) splice variant 7 (AR-V7), a truncated, constitutively active AR that mediates
oncogenic programs in a hormone-independent manner. However, mechanisms underlying altered metabolism
and AR-V7-incuded signaling in CRPC remain largely unclear. Our analyses of tumor versus paired normal
samples uncovered overexpression of YY1, a zinc-finger transcription factor, during progression of CRPC. By
genomic profiling (ChIP-seq and RNA-seq) in CRPC cells, we demonstrate that YY1 binds to and induces high
transcription of metabolic genes such as PFKP, a rate-limiting enzyme for glycolysis. Loss-of-function and
rescue studies show a YY1-PFKP axis essential for sustaining glycolysis and malignant growth of CRPC in cell
models. Additionally, YY1 interacts with AR-V7 co-occupying a majority of AR-V7 targets, where combined
actions of AR-V7 and YY1 maintain oncogenic signaling. Mass spectrometry-based identification of YY1
interactome uncovered YY1’s partners including bromodomain proteins. Knockdown of YY1, or blockade of
bromodomain proteins, suppressed CRPC growth. We hypothesize that YY1 and AR-V7 act in concert to
sustain both tumor metabolism (glycolysis)-related and AR-V7-related gene-expression programs, thereby
producing more aggressive tumor phenotypes and therapy resistance in terminal CRPCs; we also hypothesize
that targeting YY1’s co-activators reverses oncogenic signaling, providing an attractive anti-CPRC therapeutic.
Dissecting the molecular mechanisms underlying the YY1-mediated CRPC progression should provide critical
insights into new treatment strategies. Towards this goal, we will use additional models to further define the
YY1:AR-V7 co-targeted gene pathways in CRPC; validation of this finding with primary tumor samples will be
paradigm-shifting and change current views regarding how oncogenic signaling is wired in CRPC (Aim 1). We
will define YY1 as a new oncogenic factor in promoting CRPC formation and tumor cell metabolism with cell
and murine models (Aim 2). Lastly, we will determine blockade of YY1-associated co-activator machinery as
new means for treatment of CRPC (Aim 3). Because certain glycolysis pathway enzymes and YY1 cofactors
are potentially druggable with inhibitors, completion of the proposed research should not only promote a new
mechanistic understanding of CRPC but will yield innovative therapeutics for treatment of affected patients.

Grant Number: 5R01CA262903-05
NIH Institute/Center: NIH
Principal Investigator: Ling Cai