MicroRNA-185 and 342 Inhibit Tumorigenicity and Induce Apoptosis through Blockade of the SREBP Metabolic Pathway in Prostate Cancer Cells

Abstract

MicroRNA (miRNA or miR) inhibition of oncogenic related pathways has been shown to be a promising therapeutic approach for cancer. Aberrant lipid and cholesterol metabolism is involved in prostate cancer development and progression to end-stage disease. We recently demonstrated that a key transcription factor for lipogenesis, sterol regulatory element-binding protein-1 (SREBP-1), induced fatty acid and lipid accumulation and androgen receptor (AR) transcriptional activity, and also promoted prostate cancer cell growth and castration resistance. SREBP-1 was overexpressed in human prostate cancer and castration-resistant patient specimens. These experimental and clinical results indicate that SREBP-1 is a potential oncogenic transcription factor in prostate cancer. In this study, we identified two miRNAs, miR-185 and 342, that control lipogenesis and cholesterogenesis in prostate cancer cells by inhibiting SREBP-1 and 2 expression and down-regulating their targeted genes, including fatty acid synthase (FASN) and 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR). Both miR-185 and 342 inhibited tumorigenicity, cell growth, migration and invasion in prostate cancer cell culture and xenograft models coincident with their blockade of lipogenesis and cholesterogenesis. Intrinsic miR-185 and 342 expression was significantly decreased in prostate cancer cells compared to non-cancerous epithelial cells. Restoration of miR-185 and 342 led to caspase-dependent apoptotic death in prostate cancer cells. The newly identified miRNAs, miR-185 and 342, represent a novel targeting mechanism for prostate cancer therapy.

Expression of somatostatin receptor subtype 2 in growth hormone-secreting pituitary adenoma and the regulation of miR-185

“…The role of miR-185 in oncogenesis or tumor suppressor varies depending on the tumor type [32][33][34][35][36][37]. Our study found that miR-185 targeted SSTR2 mRNA to downregulate SSTR2 protein expression, promote proliferation, and inhibit apoptosis of tumor cells, which would be classified as an oncogene in pituitary adenoma cells.…”

Circulating microRNA as a marker for predicting liver disease progression in patients with chronic hepatitis B

“…For example, the impact of miRNA-342 on targeted genes including fatty acid synthase (FASN) and 3-hydroxyl-3-methylglutaryl CoA reductase (HMGCR) was reported in prostate cancer (48) . It has been demonstrated that miRNA-342 controls lipogenesis and cholesterogenesis in prostate cancer cells by preventing Sterol regulatory element-binding protein 1and 2 expression as well as down-regulating FASN and HMGCR (48) .…”

“…For example, the impact of miRNA-342 on targeted genes including fatty acid synthase (FASN) and 3-hydroxyl-3-methylglutaryl CoA reductase (HMGCR) was reported in prostate cancer (48) . It has been demonstrated that miRNA-342 controls lipogenesis and cholesterogenesis in prostate cancer cells by preventing Sterol regulatory element-binding protein 1and 2 expression as well as down-regulating FASN and HMGCR (48) . Another study has verified that miRNA-182 represents an important factor involved in HCC development and plays a vital role as an upstream regulator of the CCAAT/ enhancer binding protein alpha (C/EBPA) pathway in humans (49) by directly suppressing CEBPA to control the proliferation of tumor cells.…”

Microtargeting cancer metabolism: opening new therapeutic windows based on lipid metabolism

“…Consequently, microRNA-mediated targeting of de novo lipogenesis, including the anaplerotic pathways of the TCA, will restrain tumor growth. MicroRNA-185 and microRNA-342 have been described as regulators of lipogenesis and cholesterogenesis by targeting SREBP transcription factor in prostate cancer (PCa) cells ( 121 ). MicroRNA-613 suppresses lipogenesis by directly targeting liver X receptor ␣ in HCC HepG2 cells, suggesting that it may be a novel target for regulating lipid homeostasis ( 122 ).…”