BAZ2A-mediated repression via H3K14ac-marked enhancers promotes prostate cancer stem cells

Prostate cancer (PCa) is one of the most prevalent cancers in men. PCa is clinically unpredictable; while most tumors are indolent, others exhibit lethal phenotypes. Current treatments of metastatic disease are not curative and lead to acquired resistance and relapse. Cancer stem cells (CSC) are thought to be associated with PCa relapse and represent a target against metastatic PCa. We isolated CSCs from metastatic PCa PC3 cells based on their ability to form spheres. We determined that TIP5, a factor previously implicated in aggressive PCa, is required for the formation of PCa spheres. We determined that TIP5-bromodomain (TIP5-BRD) is an epigenetic reader of H3K14ac. TIP5 genomic occupancy in PCa cells correlates with H3K14ac. We showed that a functional TIP5-BRD is required for the transition of PCa cells from a differentiated to a stem state. Mutations of TIP5-BRD or treatment with chemical probes that abrogate TIP5-BRD association with H3K14ac impair the formation of PCa spheres. Furthermore, treatment with TIP5-BRD inhibitors impairs the oncogenic transformation mediated by Pten-loss in PCa model organoids. Genome-wide occupancy analysis shows that TIP5 interacts with promoters of repressed genes in both PCa cells and metastatic tumors and with inactive enhancers that contain H3K14ac and are associated with genes implicated in developmental processes. Our findings indicate a role of TIP5 in PCa stem cell features and suggest potential epigenetic-reader therapeutic strategies to target TIP5 in aggressive PCa. Examination of 4 different histone marks between 2 cell types (PC3 cells and PCa spheres (tumorspheres with cancer stem cell features). Genomewide occupancy of BAZ2A and BAZ2A bromodomain mutant in PC3 cells. Transcriptomic analysis of BAZ2A depletion in PC3 cells.

前列腺癌（Prostate cancer, PCa）是男性最常见的恶性肿瘤之一。前列腺癌的临床病程难以预判：多数肿瘤呈惰性生长状态，而部分肿瘤则表现出致死性表型。当前针对转移性前列腺癌的治疗手段无法实现根治，且会引发获得性耐药与肿瘤复发。癌症干细胞（Cancer stem cells, CSC）被认为与前列腺癌复发密切相关，是靶向转移性前列腺癌的潜在治疗靶点。本研究通过成球能力筛选，从转移性前列腺癌PC3细胞中分离获得癌症干细胞。研究证实，此前被发现与侵袭性前列腺癌相关的TIP5因子，是前列腺癌成球形成的必需调控因子。研究确定TIP5溴结构域（TIP5-bromodomain, TIP5-BRD）是H3K14ac的表观遗传阅读器。前列腺癌细胞中TIP5的基因组占位与H3K14ac水平呈显著正相关。研究表明，功能完整的TIP5-BRD是前列腺癌细胞从分化状态向干细胞状态转变的必要条件。TIP5-BRD的突变，或使用能够阻断TIP5-BRD与H3K14ac结合的化学探针，均会显著抑制前列腺癌成球的形成能力。此外，在前列腺癌模型类器官中，使用TIP5-BRD抑制剂可削弱PTEN缺失介导的肿瘤转化过程。全基因组结合位点分析显示，在前列腺癌细胞与转移性肿瘤中，TIP5均与沉默基因的启动子结合，同时与携带H3K14ac且与发育过程相关基因的非活性增强子存在互作。本研究结果揭示了TIP5在维持前列腺癌干细胞特性中的作用，并为侵袭性前列腺癌靶向TIP5的表观遗传阅读器类治疗策略提供了潜在可能。本数据集包含三类实验数据：一是两种细胞类型（PC3细胞与具有癌症干细胞特性的前列腺癌成球细胞，即肿瘤球）间4种不同组蛋白修饰的检测数据；二是PC3细胞中BAZ2A及其溴结构域突变体的全基因组结合位点分析数据；三是PC3细胞中BAZ2A敲降后的转录组分析数据。