E3 ligase RCHY1 negatively regulates HDAC2
Introduction
HDAC2 is an enzyme that belong to histone deacetylase class I, which is responsible for histone deacetylation [1,2]. Because HDAC2 regulates gene expression by histone acetylation, HDAC2 involved in various cellular functions including synaptic plasticity, cell proliferation, cell-cycle regulation and apoptosis [[3], [4], [5]]. In addition, deacetylation of non-histone target including p53 by HDAC2 and its role in cell fate decision have been well-established [[6], [7], [8]]. HDAC2 is one of the most promising therapeutic targets for cancer treatment since HDAC2 is overexpressed in many cancers [9,10]. On the other hands, RCHY1 is an E3 ligase that ubiquitinates various proteins for ubiquitin-mediated protein degradation [[11], [12], [13], [14]]. RCHY1 serves a role in DNA damage response by regulating proteins including p53, p21 and c-myc [15]. Although HDAC serves a role in DNA damage response, regulation of HDAC by RCHY1 is poorly understood. Here we measured the levels of class I HDAC and RCHY1 in tumors from six independent dataset using meta-analysis. Interestingly, we found the levels of HDAC2 are upregulated while the levels of RCHY1 are downregulated in tumor tissues from all dataset. Thus, we determined the levels of HDAC2 after ectopic expression of RCHY1.
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Cell culture and reagents
SW480, MCF7, H1299, HCT116 p53+/+, HCT116 p53−/−, MDA-MB231 and p53−/−mdm2−/− MEF cells were cultured in DMEM (Invitrogen) supplemented with 10% fetal bovine serum (Hyclone, GE Healthcare Life Sciences). Cells were cultured with 100U/ml penicillin and 100 mg/ml streptomycin in a humidified 5% CO2 incubator at 37 °C. The cells were sub-cultured with 0.5% trypsin and 0.02% EDTA (Sigma-Aldrich; Merck KGaA) until they reached 80% confluence. MG132, cycloheximide and VPA were purchased from Sigma.
HDAC2 is decreased by ectopic expression of RCHY1
To determine the correlation of expression levels of RCHY1 and class1 HDAC, we firstly investigated the expression level of RCHY1 and class I HDAC in cancer tissue by means of web-based meta-analyses. We analyzed six independent studies of cancer tissue against sets of neighboring normal tissue (GSE29450 [17], GSE110224 [18], GSE10799 [19], E-MEXP-882 [20], GSE23878 [21], GSE20916 [22] using GEO2R (https://www.ncbi.nlm.nih.gov/geo/geo2r) [23]. Remarkably, we found that the levels of RCHY1 are
Discussion
Although class I HDAC especially, HDAC1 and 2 have compensatory function in histone deacetylation, regulatory mechanism of HDAC2 is distinct from HDAC1 [26]. For example, CK2 phosphorylates HDAC2 but not HDAC1 and regulates dimerization of HDAC1 and 2 [27]. However, ectopic expression of RCHY1 downregulates HDAC2 as well as HDAC1 although the decrease of HDAC1 was insignificant (Fig. 1A). Inverse correlation of the levels of RCHY1 and HDAC1 was found in two datasets (ovarian and colon cancers)
Funding
This work is supported by the GeneCellPharm Corporation.
Acknowledgement
This paper resulted from the Konkuk University research support program.
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These authors contributed equally.