SOX9 Mediation of AR and ERG Driven Prostate Cancer

描述（由申请人提供）：我们和其他人之前的研究都发现了SOX9转录因子在前列腺癌（PCa）中的作用，我们最近发现SOX9是TMPRSS2中ERG的下游效应物：ERG融合阳性PCa进一步有力地支持了SOX9的主要作用。我们假设SOX9通过调节多个基因介导包括导管形态发生和干细胞/祖细胞维持在内的功能，从而促进TMPRSS2:ERG融合阳性和阴性PCa。我们的总体目标是阐明SOX9在PCa中的调控、作用和治疗意义。Aim 1的重点是进一步调节SOX9在融合阳性和阴性PCa或前体病变中表达的机制，特别是基质生长因子（包括FGFs、HGF和wnt）。我们假设，由这些机制驱动的SOX9的异常表达可能是一个可以靶向治疗的早期事件，并且可能是对雄激素剥夺治疗反应的预测性生物标志物。目标2将建立在我们初步的SOX9 ChIP- seq和转录分析研究的基础上，以确定关键基因和

DESCRIPTION (provided by applicant): Previous studies from others and us have implicated the SOX9 transcription factor in prostate cancer (PCa), and our recent identification of SOX9 as a downstream effector of ERG in TMPRSS2:ERG fusion positive PCa further strongly supports a major role for SOX9. We hypothesize that SOX9 contributes to both TMPRSS2:ERG fusion positive and negative PCa through its regulation of multiple genes that mediate functions including ductal morphogenesis and maintenance of stem/progenitor cells. Our overall goals are to elucidate the regulation, actions and therapeutic implications of SOX9 expression in PCa. Aim 1 focuses on further mechanisms that regulate SOX9 expression in fusion positive and negative PCa or precursor lesions, and in particular stromal growth factors including FGFs, HGF and Wnts. We hypothesize that the aberrant expression of SOX9 driven by these mechanisms may be an early event that can be targeted therapeutically, and may be a predictive biomarker for responses to therapies that incorporate androgen deprivation. Aim 2 will build on our preliminary SOX9 ChIP- seq and transcriptional profiling studies to identify the critical genes and pathways regulated by SOX9 in PCa. Significantly, our data indicate that SOX9 directly positively regulates the expression of multiple genes involved in Wnt signaling through the canonical Wnt/b-catenin/TCF pathway and an alternative Wnt/b-catenin/YAP1 pathway, and that it negatively regulates Wnt5a. Aim 2 will also extend our preliminary studies indicating that SOX9 regulates a series of chemokines including IL-8 that can stimulate inflammatory responses and angiogenesis. Finally, Aim 3 will use mice with prostate specific overexpression of SOX9 and clinical samples to evaluate the biological significance of SOX9 regulated genes and pathways identified in Aim 2. The specific aims are: 1) Identify molecular mechanisms regulating SOX9 expression in PCa, 2) Identify genes and pathways directly regulated by SOX9 in PCa cells, and 3) Determine the role of SOX9 regulated genes in PCa development in mice with prostate specific PTEN loss and in patient samples.