The Role of YY1 in Castration-Resistant Prostate Cancer

项目总结/文摘

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.