SUV39H1调控前列腺癌细胞迁移的表观遗传学机制研究

Prostate cancer is one of the most common cancers among men. Distant metastasis is the leading cause of prostate cancer related death. Cell migration is the key step of metastasis, thus it is of important significance for preventing and inhibiting metastasis of prostate cancer to study the mechanism of cell migration to control it. In our previous study, we found that SUV39H1, a histone methyltransferase, mediated cell migration of prostate cancer. However, the mechanism by which SUV39H1 regulating prostate cancer cell migration is still unknown. Because the function of SUV39H1 is silencing some genes through mediating the di-/tri-methylation of histone H3 at lysine 9 (H3K9me2/3), it is probably the mechanism by which SUV39H1 regulated prostate cancer cell migration. Therefore, we will discover the genes silenced by SUV39H1 through data analysis of RNA sequencing and ChIP-seq targeting H3K9me2/3 from prostate cancer cells and its SUV39H1-knockout cells, then further mine the candidate genes and pathways mediating SUV39H1's regulating prostate cancer cell migration through pathway impact analysis. And study the effect of candidate genes on prostate cancer cell migration with molecular, cellular, in vivo and histology experiments. So that uncover the epigenetic mechanism by which SUV39H1 regulated prostate cancer cell migration, and the specific targets for preventing or inhibiting the metastasis of prostate cancer.

前列腺癌是全球男性人群中最常见的癌症之一，远端转移是其主要致死因素；细胞迁移是癌转移的关键步骤，因此，研究前列腺癌细胞迁移机制、控制细胞迁移对防治前列腺癌转移至关重要。本课题组前期研究发现组蛋白甲基化转移酶SUV39H1能够调控前列腺癌细胞迁移，但其具体调控机制尚不清楚。已知该酶的功能为催化组蛋白H3第9位赖氨酸甲基化（H3K9me2/3）使相关基因表达沉默，因此，SUV39H1通过沉默何基因来调控前列腺癌细胞迁移是本研究的关键。于是，本课题组对SUV39H1敲除前后的前列腺癌细胞进行转录组测序和靶向H3K9me2/3的染色质免疫共沉淀测序，拟通过联合分析高效精准挖掘介导SUV39H1调控前列腺癌细胞迁移的沉默基因，并从分子细胞、动物水平及临床标本多层面验证研究该基因对前列腺癌细胞迁移的调控作用，从而揭示SUV39H1调控前列腺癌细胞迁移的表观遗传学机制，为前列腺癌转移的防治提供特异靶点。

前列腺癌是全球男性人群中最常见的癌症之一，远端转移是其主要致死因素；因此，研究前列腺癌细胞迁移机制、控制细胞迁移对防治前列腺癌转移至关重要。本课题组前期研究发现组蛋白甲基化转移酶SUV39H1能够调控前列腺癌细胞迁移，但其具体调控机制尚不清楚。已知该酶的功能为催化组蛋白H3第9位赖氨酸甲基化（H3K9me2/3）使相关基因表达沉默，因此，SUV39H1通过沉默何基因来调控前列腺癌细胞迁移是本研究的关键。于是，本课题组对SUV39H1敲除和过表达前后的前列腺癌细胞进行转录组测序和靶向H3K9me3的染色质免疫共沉淀测序，通过联合分析挖掘出35个介导SUV39H1调控前列腺癌细胞迁移的重要沉默基因。从分子细胞、动物水平及临床数据多层面研究和验证，发现了调控前列腺细胞迁移和增殖的重要靶基因：TYK2和CCNE2，为前列腺癌的临床防治提供潜在特异靶点。.另外，我们筛选研究发现两种药物（青蒿琥酯和伊曲康唑）显著抑制前列腺癌细胞迁移和增殖，有望成为防治前列腺癌的药物。但是，我们发现青蒿琥酯用药剂量较高时会在小鼠体内显示一定的生殖毒性，表现在抑制精子生成和睾丸缩小。类似青蒿琥酯的生殖毒性，很多抗癌药物都用一定的生理毒性。针对这一情况，我们基于增效减毒思想，合作探索开发了一种酶诱导的形态可转化药物载体，可延长药物在肿瘤部位的停留时间，降低药物对非肿瘤组织的潜在损伤；另外，针对暂无靶向药物的靶点，我们还开发了一种工程外泌体递送miRNA策略，利用相应的miRNA沉默特定靶点，期待后续能够在靶向抗癌中实现有效应用。