Journal
ONCOTARGET
Volume 7, Issue 11, Pages 12869-12884Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7331
Keywords
SREBP-2; stemness; metastasis; c-Myc; prostate cancer
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Funding
- NIH/NCI [2P01CA098912]
- Department of Defense [W81XWH-08-1-0321]
- Cedars-Sinai Garber Awards for Cancer Science
- NIH/National Center for Advancing Translational Sciences (NCATS) [UL1TR000124]
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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.
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