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.
Highlights
Prostate cancer (PCa) is the most common cancer among men in the Western world [1]
Studies have shown that the interconnections between cancerassociated PI3K/Akt/mTOR pathway and SREBPmediated metabolic signaling network contribute to a number of critical cellular functions [23,24,25]
We reported that SREBP-1 induced PCa growth and progression via the coordinated activation of lipogenesis, reactive oxygen species (ROS)/ oxidative stress and androgen receptor (AR) signaling [19]
Summary
Prostate cancer (PCa) is the most common cancer among men in the Western world [1]. The mechanisms underlying lethal PCa progression are far from being completely understood, and it is critically important to reveal the molecular basis of PCa metastatic progression to improve intervention strategies for treating this deadly disease.PCa stem cells (PCSCs) are a unique cell population residing in tumors, which are responsible for tumor initiation, relapse, metastasis and resistance to therapy [2,3,4]. PCSCs exhibit self-renewal ability and can regenerate tumorigenic progeny by regulating a number of developmental signaling pathways including PTEN/ PI3K/Akt [5], p53 [6] and NF-κB [7] pathways as well as by expressing stemness-related genes such as c-Myc [8], aldehyde dehydrogenase 1A1 (ALDH1A1) [9], CD44 [10], NANOG [11] and SOX-2 [12], which participate in maintaining the stem cell characteristics of cancer cells These markers and regulators of stemness have been implicated in PCa metastatic progression and offer potential therapeutic targets for the treatment of PCa [13, 14]. SREBP-1 induced PCa growth and progression through concerted activation of the metabolic signaling networks involving androgen receptor (AR), lipogenesis and oxidative stress www.impactjournals.com/oncotarget
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