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Epigenetic silencing of miR-137 induces resistance to bicalutamide by targeting TRIM24 in prostate cancer cells.

ABSTRACT: Prostate cancer is an important hormone-dependent cancer affecting men. In the initial stages, prostate cancer is often treated using hormone therapy, including bicalutamide. Despite the initial effectiveness of this therapy, the tumor eventually acquires resistance, resulting in recurrence of castration-resistant prostate cancer (CRPC). Dysregulation of microRNA (miRNA) function is one of the putative underlying mechanisms of hormone therapy resistance. Reports have shown that miRNAs act as tumor suppressors in patients with prostate cancer, but the role of these molecules in bicalutamide resistance in prostate cancer cell lines remains unclear. We performed lentiviral miRNA library screening to identify novel miRNAs that modulate the response of human prostate cancer LNCaP cells to the antiandrogen bicalutamide. We found that the tumor suppressor miRNA miR-137 silenced signaling in a spectrum of human cancers and selectively targeted tripartite motif-containing 24 (TRIM24) to suppress tumor proliferation. Silencing of TRIM24 recapitulated the effect of miR-137 on cell proliferation, whereas overexpression of TRIM24 reversed this effect. Real-time reverse transcription PCR analysis revealed a reciprocal relationship between miR-137 and TRIM24 in prostate cancer cell lines and tissues. Mechanistic studies indicated that methyl CpG-binding protein 2 (MeCP2) and DNA methyltransferases (DNMTs) cooperate to promote methylation of the miR-137 promoter and the consequent decreased transcription, leading to enhanced TRIM24 expression and glutamine metabolism. These findings describe a novel mechanism that affects TRIM24 deregulation in human cancers and provide a molecular link between miR-137, TRIM24, and tumor proliferation in CRPC.

SUBMITTER: Guan Y

PROVIDER: S-EPMC6556665 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Epigenetic silencing of miR-137 induces resistance to bicalutamide by targeting TRIM24 in prostate cancer cells.

Guan Yonghui Y Guan Xiaoyue X An Hengqing H Baihetiya Azhati A Wang Wenguang W Shao Weimin W Yang Haiou H Wang Yujie Y

American journal of translational research 20190515 5

Prostate cancer is an important hormone-dependent cancer affecting men. In the initial stages, prostate cancer is often treated using hormone therapy, including bicalutamide. Despite the initial effectiveness of this therapy, the tumor eventually acquires resistance, resulting in recurrence of castration-resistant prostate cancer (CRPC). Dysregulation of microRNA (miRNA) function is one of the putative underlying mechanisms of hormone therapy resistance. Reports have shown that miRNAs act as tum ...[more]

PMID: 31217891

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Project description:Bicalutamide (BIC) resistance impedes the treatment of prostate cancer (PCa) and seems to involve ferroptosis; however, the underlying mechanism remains unclear. Our study aimed to explore how miR-15b-3p modulates ferroptosis in response to BIC resistance and determine whether the miRNA is suitable for early screening of PCa. Here, we found that PCa tissues had significantly higher miR-15b-3p expression than adjacent normal tissues. Analysis of blood samples in patients who underwent prostate-specific antigen (PSA) screening revealed that miR-15b-3p was a more accurate diagnostic than PSA (miR-15b-3p area under the curve [AUC] = 0.941, PSA AUC = 0.815). In vitro experiments then demonstrated that miR-15b-3p expression was markedly higher in LNCaP, PC-3, and DU145 cells than in RWPE-1 cells. Treatment with BIC decreased miR-15b-3p expression and progressive ferroptosis. Mechanistically, we identified KLF2 as the downstream target of miR-15b-3p. Overexpressing KLF2 facilitated ferroptosis via augmenting MDA and iron concentrations, in turn inhibiting the SLC7A11/GPX4 axis and decreasing GSH concentration. Through modulating ferroptosis, miR-15b-3p mimic and inhibitor weakened and enhanced BIC sensitivity, respectively. Furthermore, BIC treatment limited xenograft tumor volume in vivo, whereas agomir-15b-3p promoted tumor growth, indicating that miR-15b-3p attenuated the tumor-suppressive effects of BIC. Taken together, our results suggested that miR-15b-3p is crucial to BIC resistance, specifically via targeting KLF2 and thereby suppressing ferroptosis. High miR-15b-3p expression in early PCa screening should reflect a higher probability of cancer. In conclusion, miR-15b-3p has strong potential as a screening and diagnostic biomarker with reliable prospects for clinical application. Furthermore, because patients with high miR-15b-3p and low KLF2 expression have a greater risk of BIC resistance and malignant progression, targeting the miRNA and its downstream protein may be a new treatment strategy.

Dataset Information

Epigenetic silencing of miR-137 induces resistance to bicalutamide by targeting TRIM24 in prostate cancer cells.

Publications

Epigenetic silencing of miR-137 induces resistance to bicalutamide by targeting TRIM24 in prostate cancer cells.

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