title: SREBP-2 promotes stem cell-like properties and metastasis by transcriptional activation of c-Myc in prostate cancer.
abstract: 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.
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Xiangyan
authors.initials: X
authors.lastname: Li
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Jason Boyang
authors.initials: JB
authors.lastname: Wu
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.|Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Qinlong
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Urology, Kobe University Graduate School of Medicine, Chuo-Ku, Kobe, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Shigemura
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Wen-Chin
authors.initials: WC
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D015533:Transcriptional Activation; D023041:Xenograft Model Antitumor Assays
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2
keywords: SREBP-2; c-Myc; metastasis; prostate cancer; stemness