google-site-verification=3yOPxHLzVxSybZz1mYEONX7tx5RllruREij4EIwylHY

Hypermethylated in cancer 1 (HIC1) mediates high glucose induced ROS accumulation in renal tubular epithelial cells by epigenetically repressing SIRT1 transcription

Biochim Biophys Acta Gene Regul Mech. 2018 Oct;1861(10):917-927. doi: 10.1016/j.bbagrm.2018.08.002. Epub 2018 Aug 25.

Hypermethylated in cancer 1 (HIC1) mediates high glucose induced ROS accumulation in renal tubular epithelial cells by epigenetically repressing SIRT1 transcription.

Zeng S1Wu X1Chen X1Xu H1Zhang T2Xu Y3.

Author information

Abstract

Reactive oxygen species (ROS) is a key regulator of an array of physiological and pathological processes. While essential for the host defense mechanism, excessive ROS generation and/or deficient clearance is blamed for the pathogenesis of human diseases. In the present study, we investigated the regulatory role of hypermethylated in cancer 1 (HIC1), a transcription factor, in high glucose-induced ROS accumulation in renal tubular epithelial cells (HK-2). Treatment with high glucose (HG) not only markedly up-regulated HIC1 expression but prompted its translocation into the nucleus. HG stimulation promoted HIC1 binding to the promoter of SIRT1, a known HIC1 target with anti-oxidative ability. The recruitment of HIC1 to the SIRT1 promoter was paralleled by the enrichment of trimethylated histone H3K27 and 5?methyl cytosine, two well-characterized markers for trans-repression. HIC1 silencing with small interfering RNA abrogated SIRT1 repression by HG and at the same time weakened ROS accumulation in HK-2 cells. Knockdown or pharmaceutical inhibition of SIRT1 preempted the effect of HIC1 depletion by restoring ROS accumulation and down-regulating the expression of antioxidant genes. Mechanistically, HIC1 interacted with and recruited EZH2, an H3K27 trimethyltransferase, and DNA methyltransferase 1 (DNMT1) to repress SIRT1 transcription in response to HG stimulation. Depletion or inhibition of EZH2 or DNMT1 rescued SIRT1 expression and blocked ROS accumulation in HG-treated HK-2 cells. In conclusion, our data suggest that epigenetic repression of SIRT1 by HIC1 may contribute to HG-induced elevation of ROS levels in renal tubular epithelial cells.

KEYWORDS: 

DNA methylation; Epigenetics; Histone methylation; ROS; Renal tubular epithelial cell; Transcriptional regulation

PMID: 30496037  DOI: 10.1016/j.bbagrm.2018.08.002

[Indexed for MEDLINE] 

© drbob 2018