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Hypoxia-inducible miR-182 enhances HIF1? signaling via targeting PHD2 and FIH1 in prostate cancer.

ABSTRACT: Activation of hypoxia-inducible factor 1? (HIF1?) controls the transcription of genes governing angiogenesis under hypoxic condition during tumorigenesis. Here we show that hypoxia-responsive miR-182 is regulated by HIF1? at transcriptional level. Prolyl hydroxylase domain enzymes (PHD) and factor inhibiting HIF-1 (FIH1), negative regulators of HIF1 signaling, are direct targets of miR-182. Overexpression of miR-182 in prostate cancer cells led to a reduction of PHD2 and FIH1 expression and an increase in HIF1? level either under normoxic or hypoxic condition. Consistently, inhibition of miR-182 could increase PHD2 and FIH1 levels, thereby reducing the hypoxia-induced HIF1? expression. Matrigel plug assay showed that angiogenesis was increased by miR-182 overexpression, and vice versa. miR-182 overexpression in PC-3 prostate cancer xenografts decreased PHD2 and FIH1 expression, elevated HIF1? protein levels, and increased tumor size. Lastly, we revealed that the levels of both miR-182 and HIF1? were elevated, while the expression PHD2 and FIH1 was downregulated in a mouse model of prostate cancer. Together, our results suggest that the interplay between miR-182 and HIF1? could result in a sustained activation of HIF1? pathway, which might facilitate tumor cell adaption to hypoxic stress during prostate tumor progression.

SUBMITTER: Li Y

PROVIDER: S-EPMC4513346 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Hypoxia-inducible miR-182 enhances HIF1α signaling via targeting PHD2 and FIH1 in prostate cancer.

Li Yan Y Zhang Duo D Wang Xiaoyun X Yao Xuan X Ye Cheng C Zhang Shengjie S Wang Hui H Chang Cunjie C Xia Hongfeng H Wang Yu-Cheng YC Fang Jing J Yan Jun J Ying Hao H

Scientific reports 20150724

Activation of hypoxia-inducible factor 1α (HIF1α) controls the transcription of genes governing angiogenesis under hypoxic condition during tumorigenesis. Here we show that hypoxia-responsive miR-182 is regulated by HIF1α at transcriptional level. Prolyl hydroxylase domain enzymes (PHD) and factor inhibiting HIF-1 (FIH1), negative regulators of HIF1 signaling, are direct targets of miR-182. Overexpression of miR-182 in prostate cancer cells led to a reduction of PHD2 and FIH1 expression and an i ...[more]

PMID: 26205124

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Project description:Prolyl hydroxylase domain 2 (PHD2) is deemed a primary oxygen sensor in humans, yet many details of its underlying mechanism are still not fully understood. (Fe(2+) + ?KG)PHD2 is 6-coordinate, with a 2His/1Asp facial triad occupying three coordination sites, a bidentate ?-ketoglutarate occupying two sites, and an aquo ligand in the final site. Turnover is thought to be initiated upon release of the aquo ligand, creating a site for O(2) to bind at the iron. Herein we show that steady-state turnover is faster under acidic conditions, with k(cat) exhibiting a kinetic pK(a) = 7.22. A variety of spectroscopic probes were employed to identify the active-site acid, through comparison of (Fe(2+) + ?KG)PHD2 at pH 6.50 with pH 8.50. The near-UV circular dichroism spectrum was virtually unchanged at elevated pH, indicating that the secondary structure did not change as a function of pH. UV-visible and Fe X-ray absorption spectroscopy indicated that the primary coordination sphere of Fe(2+) changed upon increasing the pH; extended X-ray absorption fine structure analysis found a short Fe-(O/N) bond length of 1.96 Å at pH 8.50, strongly suggesting that the aquo ligand was deprotonated at this pH. Solvent isotope effects were measured during steady-sate turnover over a wide pH-range, with an inverse solvent isotope effect (SIE) of k(cat) observed ((D(2)O)k(cat) = 0.91 ± 0.03) for the acid form; a similar SIE was observed for the basic form of the enzyme ((D(2)O)k(cat) = 0.9 ± 0.1), with an acid equilibrium offset of ?pK(a) = 0.67 ± 0.04. The inverse SIE indicated that aquo release from the active site Fe(2+) immediately precedes a rate-limiting step, suggesting that turnover in this enzyme may be partially limited by the rate of O(2) binding or activation, and suggesting that aquo release is relatively slow. The unusual kinetic pK(a) further suggested that PHD2 might function physiologically to sense both intracellular pO(2) as well as pH, which could provide for feedback between anaerobic metabolism and hypoxia sensing.

Dataset Information

Hypoxia-inducible miR-182 enhances HIF1? signaling via targeting PHD2 and FIH1 in prostate cancer.

Publications

Hypoxia-inducible miR-182 enhances HIF1α signaling via targeting PHD2 and FIH1 in prostate cancer.

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