组蛋白修饰效应分子PHF19在前列癌内分泌治疗耐受中功能及机制研究

Prostate adenocarcinoma, one of the most common cancers affects aging men. Current treatments for that target androgen receptor (AR) signaling improve patient survival, yet ultimately lead to castration-resistant prostate cancer (CRPC). The transition from castration-resistant prostate adenocarcinoma to neuroendocrine prostate cancer (NEPC) has emerged as an important mechanism of treatment resistance. Despite recent progress, the mechanism underlying prostate cancer lineage plasticity and the development of CRPC remains to be defined. Here, we undertook a chromatin focused epigenetic library screen, and identified that PHD Finger Protein 19 (PHF19) is involved in CRPC. PHF19 is known to specifically bind histone H3 trimethylated at Lys-36 (H3K36me3) and recruits the PRC2 complex to control gene transcription. Our preliminary results indicated that PHF19 downregulation facilitated the transformation of prostate adenocarcinoma into NEPC under androgen deprivation treatment, and thereby led to the cells developing into CRPC. Thus, we propose that PH19 serves as a critical epigenetic regulator to modulate cell plasticity during CRPC development. In this application, we aim to utilize cell cultures, genetically engineered mouses (GEMs), organoid assays together with patient specimen analysis to characterize the functional role of PHF19 in CPRC with a prime focus in cell plasticity. Further mechanistic characterization will help us to identify key modulator involved in neuroendocrine differentiation during CRPC. Lineage plasticity is proposed to drive prostate cancer progression by enabling adaptation to selective pressures experienced during metastasis and androgen deprivation therapy (ADT). Thus, success accomplishment of proposed the goal will provide rationale for the development of therapeutic strategies for treating this aggressive subtype of prostate cancer.

前列腺癌是严重危害男性健康的常见肿瘤。临床上多采用雄激素剥夺的内分泌疗法治疗前列腺癌。但多数患者会对治疗耐受，并因此死亡。研究表明腺瘤向神经内分泌细胞转分化是耐受产生的重要原因之一。本项目聚焦表观遗传调控在前列腺癌内分泌治疗耐受中的功能及调控机制。前期通过文库筛选，我们发现组蛋白修饰效应分子PHF19敲低可使对雄激素敏感的前列腺癌细胞LNCaP耐受雄激素剥夺处理。研究结果揭示PHF19调节腺瘤向神经内分泌肿瘤细胞转分化，影响内分泌治疗耐受。与此一致，小鼠中PHF19敲除可导致前列腺癌内分泌治疗耐受。基于前期工作基础，本项目拟通过细胞、遗传小鼠和类器官等模型进一步揭示PHF19在前列腺癌内分泌治疗耐受中的功能，阐明PHF19缺失促进细胞转分化导致内分泌治疗耐受的分子机理。希望通过本项目的研究进一步诠释内分泌治疗耐受中腺瘤向神经内分泌肿瘤细胞转分化的分子机制，为前列腺癌临床干预提供理论依据。

前列腺癌是一类严重危害男性健康的常见肿瘤。临床上多采用雄激素剥夺的内分泌治疗手段来治疗前列腺癌。但多数患者会在治疗后产生耐受，并因此死亡。近年来的研究表明，腺瘤向神经内分泌细胞转分化是产生耐受的一项重要原因。通过筛选表观遗传修饰相关基因的文库发现PHD锌指蛋白PHF19敲除可使对雄激素敏感的前列腺癌细胞耐受雄激素剥夺处理。更重要的是，雄激素剥夺处理下PHF19敲低可以改变细胞可塑性，促进腺瘤向神经内分泌肿瘤细胞转分化，导致内分泌治疗耐受。与此相一致，小鼠中PHF19敲除（PTENPC-/-; PHF19PC-/-）可以导致前列腺癌内分泌治疗耐受。分子机制上，PHF19敲低显著减少SOX2启动子区H3K27me3结合，上调SOX2表达促进NEPC。不仅如此，在临床NEPC样本中，PHF19与SOX2表达也呈现负相关关系。本项目的研究进一步诠释了内分泌治疗耐受中腺瘤向神经内分泌肿瘤细胞转分化的分子机制，为前列腺癌临床干预提供理论基础。.除此之外，项目研究中还发现PHF19互作蛋白BRG1与PTEN在前列腺癌中发挥协同致死的作用；靶向BRG1可以作为潜在的治疗PTEN缺失前列腺肿瘤的手段。同时揭示PHF19互作蛋白H3K36甲基转移酶SETD2响应外界能量信号调控EZH2表达水平，从而抑制前列腺癌转移的分子机制。项目研究在遗传和表观遗传层面系统性地解析前列腺癌发生、高侵袭性转移和对雄激素剥夺疗法抵抗的机制，从而最终为肿瘤的预警、诊断和治疗提供新的分子靶标和策略。..