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Abstract：
Special AT-rich sequence binding protein-2 (SATB2) is a nuclear matrix protein that binds to nuclear attachment regions and is involved in chromatin remodeling and transcription regulation. In stem cells, it regulates the expression of genes required for maintaining pluripotency and self-renewal and epithelial-mesenchymal transition (EMT). In this study, we examined the oncogenic role of SATB2 in prostate cancer and assessed whether overexpression of SATB2 in human normal prostate epithelial cells (PrECs) induces properties of cancer stem cells (CSCs). The results demonstrate that SATB2 is highly expressed in prostate cancer cell lines and CSCs, but not in PrECs. Overexpression of SATB2 in PrECs induces cellular transformation which was evident by the formation of colonies in soft agar and spheroids in suspension. Overexpression of SATB2 in PrECs also resulted in induction of stem cell markers (CD44 and CD133), pluripotency-maintaining transcription factors (cMYC, OCT4, SOX2, KLF4, and NANOG), CADHERIN switch, and EMT-related transcription factors. Chromatin immunoprecipitation assay demonstrated that SATB2 can directly bind to promoters of BCL-2, BSP, NANOG, MYC, XIAP, KLF4, and HOXA2, suggesting SATB2 is capable of directly regulating pluripotency/self-renewal, cell survival, and proliferation. Since prostate CSCs play a crucial role in cancer initiation, progression, and metastasis, we also examined the effects of SATB2 knockdown on stemness. SATB2 knockdown in prostate CSCs inhibited spheroid formation, cell viability, colony formation, cell motility, migration, and invasion compared to their scrambled control groups. SATB2 knockdown in CSCs also upregulated the expression of E-CADHERIN and inhibited the expression of N-CADHERIN, SNAIL, SLUG, and ZEB1. The expression of SATB2 was significantly higher in prostate adenocarcinoma compared to normal tissues. Overall, our data suggest that SATB2 acts as an oncogenic factor where it is capable of inducing malignant changes in PrECs by inducing CSC characteristics.
摘要：
特殊的富含AT的序列结合蛋白2（SATB2）是一种与核附着区结合的核基质蛋白，参与染色质重塑和转录调控。在干细胞中，它调节维持多能性和自我更新以及上皮-间质转化（EMT）所需的基因的表达。在这项研究中,我们研究了SATB2在前列腺癌中的致癌作用,并评估了SATB2在人正常前列腺上皮细胞(PrECs)中的过表达是否诱导了癌症干细胞(CSC)的特性.结果表明，SATB2在前列腺癌细胞系和CSC中高表达，但不是在Precs中。SATB2在PrEC中的过表达诱导细胞转化，这通过在软琼脂中形成菌落和在悬浮液中形成球状体来证明。SATB2在PrECs中的过表达也导致干细胞标记（CD44和CD133）的诱导，多能性维持转录因子(cMYC，OCT4、SOX2、KLF4和NANOG)，CADHERIN开关,和EMT相关转录因子。染色质免疫沉淀实验证明SATB2可以直接与BCL-2、BSP、南诺,MYC,XIAP,KLF4和HOXA2，表明SATB2能够直接调节多能性/自我更新，细胞存活,和扩散。由于前列腺CSC在癌症发生中起着至关重要的作用，programming,和转移，我们还研究了SATB2敲低对干性的影响。SATB2敲低在前列腺CSCs抑制球体形成，细胞活力，菌落形成,细胞运动性,迁移,和入侵与他们混乱的对照组相比。在CSCs中SATB2敲低也上调E-CADHERIN的表达和抑制N-CADHERIN的表达,蜗牛,SLUG,ZEB1SATB2在前列腺腺癌中的表达明显高于正常组织。总的来说,我们的数据表明,SATB2作为一种致癌因子,能够通过诱导CSC特征诱导PrECs的恶性改变.
