Dataset Information

BMI1 Drives Steroidogenesis Through Epigenetically Repressing the p38 MAPK Pathway.

ABSTRACT: Testosterone biosynthesis progressively decreases in aging males primarily as a result of functional changes to Leydig cells. Despite this, the mechanisms underlying steroidogenesis remain largely unclear. Using gene knock-out approaches, we and others have recently identified Bmi1 as an anti-aging gene. Herein, we investigate the role of BMI1 in steroidogenesis using mouse MLTC-1 and primary Leydig cells. We show that BMI1 can positively regulate testosterone production. Mechanistically, in addition to its known role in antioxidant activity, we also report that p38 mitogen-activated protein kinase (MAPK) signaling is activated, and testosterone levels reduced, in BMI1-deficient cells; however, the silencing of the p38 MAPK pathway restores testosterone production. Furthermore, we reveal that BMI1 directly binds to the promoter region of Map3k3, an upstream activator of p38, thereby modulating its chromatin status and repressing its expression. Consequently, this results in the inhibition of the p38 MAPK pathway and the promotion of steroidogenesis. Our study uncovered a novel epigenetic mechanism in steroidogenesis involving BMI1-mediated gene silencing and provides potential therapeutic targets for the treatment of hypogonadism.

SUBMITTER: Yu J

PROVIDER: S-EPMC8076678 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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BMI1 Drives Steroidogenesis Through Epigenetically Repressing the p38 MAPK Pathway.

Yu Jun J Wu Yibo Y Li Hong H Zhou Hui H Shen Cong C Gao Tingting T Lin Meng M Dai Xiuliang X Ou Jian J Liu Meiling M Huang Xiaoyan X Zheng Bo B Sun Fei F

Frontiers in cell and developmental biology 20210413

Testosterone biosynthesis progressively decreases in aging males primarily as a result of functional changes to Leydig cells. Despite this, the mechanisms underlying steroidogenesis remain largely unclear. Using gene knock-out approaches, we and others have recently identified <i>Bmi1</i> as an anti-aging gene. Herein, we investigate the role of BMI1 in steroidogenesis using mouse MLTC-1 and primary Leydig cells. We show that BMI1 can positively regulate testosterone production. Mechanistically, ...[more]

PMID: 33928089

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Project description:Extensive research has demonstrated a tumor-promoting role of increased WNT5A expression in malignant melanoma. However, very little light has been shed upon how WNT5A expression is up-regulated in melanoma. A potential regulator of WNT5A expression is the pro-inflammatory cytokine Interleukin (IL)-6, which shares the ability of WNT5A to increase melanoma cell invasion. Here, we investigate whether IL-6 can promote melanoma cell motility through an increased expression of WNT5A. We clearly demonstrate that the WNT5A-antagonistic peptide Box5 could inhibit IL-6-induced melanoma cell migration and invasion. Furthermore, IL-6 stimulation of the human melanoma cell lines HTB63 and A375 increased the expression of WNT5A in a dose-dependent manner. To identify the signaling mechanism responsible for this up-regulation, we explored the involvement of the three main signals induced by IL-6; STAT3, Akt and ERK 1/2. Of these, only STAT3 was activated by IL-6 in the melanoma cell lines tested. However, the STAT3 inhibitor S3I-201 failed to inhibit IL-6-induced WNT5A up-regulation in HTB63 and A375 cells. Nor did STAT3 siRNA silencing affect the expression of WNT5A. In search of an alternative signaling mechanism, we detected IL-6-induced activation of p38-MAPK in HTB63 and A375 cells. The p38-MAPK inhibitor SB203580 abolished the IL-6-induced WNT5A up-regulation and blocked IL-6-induced melanoma cell invasion. The latter effect could be rescued by the addition of recombinant WNT5A. Notably, immunoprecipitation analysis revealed that only the p38?-MAPK isoform was activated by IL-6, and subsequent siRNA silencing of p38?-MAPK abolished the IL-6-induced up-regulation of WNT5A. Taken together, we demonstrate a novel link between the two melanoma pro-metastatic agents IL-6 and WNT5A explaining how IL-6 can increase melanoma cell invasion and thus promote the metastatic process. This finding provides a basis for future therapeutic intervention of melanoma progression.

Dataset Information

BMI1 Drives Steroidogenesis Through Epigenetically Repressing the p38 MAPK Pathway.

Publications

BMI1 Drives Steroidogenesis Through Epigenetically Repressing the p38 MAPK Pathway.

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