SREBP-2 promotes stem cell-like properties and metastasis by transcriptional activation of c-Myc in prostate cancer.
SREBP-2 promotes stem cell-like properties and metastasis by transcriptional activation of c-Myc in prostate cancer.
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DOI：
10.18632/oncotarget.7331
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发表时间：
2016-03-15
期刊：
影响因子：
--
通讯作者：
Huang WC
中科院分区：
文献类型：
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作者：
Li X;Wu JB;Li Q;Shigemura K;Chung LW;Huang WC
固醇调节元件结合蛋白-2(SREBP-2)转录因子主要控制正常细胞中胆固醇的生物合成和动态平衡。SREBP-2在致死性前列腺癌(PCA)进展中的作用尚不清楚。在这里，我们发现SREBP-2的表达在晚期病理分级和转移性前列腺癌中升高，并与不良的临床结果显著相关。生物学功能分析表明，SREBP-2可诱导PCa细胞增殖、侵袭和迁移。此外，SREBP-2的过表达增加了PCa干细胞的数量、前哨形成能力和致瘤能力，而SREBP-2的基因沉默抑制了PCa细胞的生长、干细胞的生长和异种移植瘤的生长和转移。临床和机制研究表明，SREBP-2与c-Myc呈正相关，并通过直接与c-Myc启动子5‘侧翼的SREBP-2结合元件相互作用而诱导c-Myc的激活，从而驱动肿瘤的干性和转移。总之，这些临床和实验结果揭示了SREBP-2在诱导干细胞样表型和PCa转移中的新作用，通过将SREBP-2作为一种有前景的治疗方法来阐明翻译潜力。
Sterol regulatory element-binding protein-2 (SREBP-2) transcription factor mainly controls cholesterol biosynthesis and homeostasis in normal cells. The role of SREBP-2 in lethal prostate cancer (PCa) progression remains to be elucidated. Here, we showed that expression of SREBP-2 was elevated in advanced pathologic grade and metastatic PCa and significantly associated with poor clinical outcomes. Biofunctional analyses demonstrated that SREBP-2 induced PCa cell proliferation, invasion and migration. Furthermore, overexpression of SREBP-2 increased the PCa stem cell population, prostasphere-forming ability and tumor-initiating capability, whereas genetic silencing of SREBP-2 inhibited PCa cell growth, stemness, and xenograft tumor growth and metastasis. Clinical and mechanistic data showed that SREBP-2 was positively correlated with c-Myc and induced c-Myc activation by directly interacting with an SREBP-2-binding element in the 5′-flanking c-Myc promoter region to drive stemness and metastasis. Collectively, these clinical and experimental results reveal a novel role of SREBP-2 in the induction of a stem cell-like phenotype and PCa metastasis, which sheds light on translational potential by targeting SREBP-2 as a promising therapeutic approach in PCa.