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.
Highlights
MicroRNA is a short, single stranded and endogenously occurring non-coding RNA that regulates post-transcriptional gene expression by complementary base pairing at 39 untranslated regions (UTR) of target mRNAs [1,2]
To further verify if miR-185 and 342 directly bind with 39 UTRs of sterol regulatory elementbinding protein-1 (SREBP-1) and Sterol regulatory element-binding protein (SREBP)-2, we performed 39 UTR luciferase reporter assay and found that the relative 39 UTR luciferase activities of both SREBP-1 and SREBP-2 were significantly decreased in miR-185 and 342 transfected prostate cancer cells (Fig. S1B)
The results confirm that SREBP-1 and SREBP-2 mRNAs are direct targets of miR-185 and 342
Summary
MicroRNA (miRNA or miR) is a short (average 22 nt), single stranded and endogenously occurring non-coding RNA that regulates post-transcriptional gene expression by complementary base pairing at 39 untranslated regions (UTR) of target mRNAs [1,2]. Certain miRNA species, such as miR-20a, 23b, 34a, 126, 145, 146a, 221 and 222, are aberrantly expressed in prostate cancer [9,10]. A number of miRNAs have been demonstrated to contribute to tumor initiation, growth and lethal progression [11,12,13,14,15]. These discoveries provide a rationale for considering the efficacy of miRNA-based replacement therapies, with the goal of inhibiting oncogenes and their related pathways, or restoring tumor suppressor genes
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