MicroRNA-21 deficiency suppresses prostate cancer progression through downregulation of the IRS1-SREBP-1 signaling pathway

• Published in: Cancer letters Vol. 525; pp. 46 - 54
• Main Authors: Kanagasabai, Thanigaivelan, Li, Guoliang, Shen, Tian Huai, Gladoun, Nataliya, Castillo-Martin, Mireia, Celada, Sherly I., Xie, Yingqiu, Brown, Lakendria K., Mark, Zaniya A., Ochieng, Josiah, Ballard, Billy R., Cordon-Cardo, Carlos, Adunyah, Samuel E., Jin, Renjie, Matusik, Robert J., Chen, Zhenbang
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.01.2022; Elsevier Limited
• Subjects: ACC; Acetyl-CoA carboxylase; Acetyl-CoA Carboxylase - genetics; Age; Animal models; Animals; Apoptosis; Cell cycle; Cell growth; Cell migration; Cell proliferation; Cell Proliferation - genetics; Disease Progression; Embryo fibroblasts; FASN; Fatty acid signaling and mouse models; Fatty Acid Synthase, Type I - genetics; Fatty-acid synthase; Fibroblasts; Gene Expression Regulation, Neoplastic - genetics; Genes; Heterografts; Humans; Insulin; Insulin receptor substrate 1; Insulin Receptor Substrate Proteins - genetics; Lipid metabolism; Lipogenesis; Male; Malignancy; Medical prognosis; Metastasis; Mice; MicroRNAs; MicroRNAs - genetics; miRNA; Mutants; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Proteins; PTEN; PTEN protein; Senescence; Signal Transduction; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol regulatory element-binding protein; Sterols; TP53; Tumorigenesis; Tumors; United States > US; PTEN; ACC; Fatty acid signaling and mouse models; TP53; FASN
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.09.041

Sterol regulatory element-binding protein 1 (SREBP-1), a master transcription factor in lipogenesis and lipid metabolism, is critical for disease progression and associated with poor outcomes in prostate cancer (PCa) patients. However, the mechanism of SREBP-1 regulation in PCa remains elusive. Here, we report that SREBP-1 is transcriptionally regulated by microRNA-21 (miR-21) in vitro in cultured cells and in vivo in mouse models. We observed aberrant upregulation of SREBP-1, fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC) in Pten/Trp53 double-null mouse embryonic fibroblasts (MEFs) and Pten/Trp53 double-null mutant mice. Strikingly, miR-21 loss significantly reduced cell proliferation and suppressed the prostate tumorigenesis of Pten/Trp53 mutant mice. Mechanistically, miR-21 inactivation decreased the levels of SREBP-1, FASN, and ACC in human PCa cells through downregulation of insulin receptor substrate 1 (IRS1)-mediated transcription and induction of cellular senescence. Conversely, miR-21 overexpression increased cell proliferation and migration; as well as the levels of IRS1, SREBP-1, FASN, and ACC in human PCa cells. Our findings reveal that miR-21 promotes PCa progression by activating the IRS1/SREBP-1 axis, and targeting miR-21/SREBP-1 signaling pathway can be a novel strategy for controlling PCa malignancy. •miR-21 deficiency suppresses prostate cancer progression in Pten/Trp53 double null mutant mice.•miR-21 loss decreases the levels of SREBP-1, FASN and ACC through downregulation of IRS1-mediated transcription to reduce the proliferation of prostate cancer cells.•Enforced overexpression of miR-21 increases levels of SREBP-1, FASN and ACC in human prostate cells.•miR-21 inhibition decreases cell proliferation, the IRS1/SREBP-a signaling, and lipogenesis in prostate cancer cells.