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

Publication date: Available online 25 August 2018

Source: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms

Author(s): Sheng Zeng, Xiaoyan Wu, Xuyan Chen, Huihui Xu, Tao Zhang, Yong Xu

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.

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