br Materials and methods br Results br

Materials and methods
Results
Discussion Type I ECa is associated with estrogen excess, obesity and hormone-receptor positivity. However, the function of ERα on ECa is considered complicated. The expression of ERα is reduced in grade III ECa clinical samples [13]. The high ERα expression is associated with long disease-free survival [15]. In this study, our results found that MOF expression is reduced and lower expression of MOF is associated with higher grade in ECa (Fig. 2). Moreover, MOF expression is positively correlated with ERα expression (Fig. 2) and MOF is involved in maintenance of ERα stability in ECa (Fig. 3). These data suggested that MOF reduction may contribute to decreased expression of ERα in higher grade ECa tissues. In breast cancer, G9a has been identified as an ERα co-activator associated with PHF20/MOF complex [25]. Our data demonstrated that MOF functions as a transcriptional activator of DRAM1 and TAGLN, which are induced by E2 treatment, in ECa (Fig. 4). Moreover, we have detected that MOF is recruited to the promoter region of DRAM1 carrying estrogen response element (DRAM1-EREI), and mediates histone H4K16 acetylation on DRAM1-EREI, which is consistent with previous report that MOF HAT complex are recruited to ERα target gene promoters in breast cancer [25]. Typically, DRAM1 is a direct target gene of p53 and a critical factor for p53-dependent apoptosis and autophagy [26]. TAGLN, an actin-binding protein, decreases the proliferation potential of breast cancer [27] and increases apoptosis of prostate cancer glucose transporter [28]. These data suggest that MOF-mediated regulation of a subset of ERα-induced genes may contribute to suppression of cell growth and proliferation in ECa, which provides a possible mechanism for the association between high ERα expression and good prognosis. MOF is responsible for acetylation on several non-histone proteins, such as p53 and Nrf2 [9,10]. p300 induces acetylation of ERα, and acetylation of ERα is accompanied by an increased stability of ERα protein. Our results revealed that in addition to p300, ERα was also acetylated by MOF and the acetylation of ERα by MOF is related to maintenance of ERα stability. (Fig. 3).
Conflicts of interest
Funding This work was supported by National Natural Science Foundation of China [31701102for Shengli Wang, 81702800for Renlong Zou, 81371271for Shu-yan Cong], Foundation for Special Professor of Liaoning Province (the 5th batch) for Yue Zhao, Liaoning Provincial Natural Science Foundation of China [20180550810] for Yi Wu, and Key Laboratory Grant of Education Department of Liaoning Province (LS201602) for Xin Zhou.
Acknowledgments
Introduction Arsenic, as a ubiquitous element, ranks the 20th most abundant element in the earth's crust (Mandal and Suzuki, 2002). Human exposure to environmental arsenic occurs primarily via ingestion of inorganic arsenic contaminated water. It is estimated that over 200 million individuals worldwide are exposed to drinking water containing arsenic above 10 μg/L, the safety standard set by the World Health Organization (Argos et al., 2014). Through numerous epidemiological investigations, accumulating evidence demonstrate the positive relationship between inorganic arsenic and carcinomas, including both skin and internal cancers. In Wisconsin, USA, residents who were over 35 years old and consumed arsenic-contaminated water for more than a decade suffered a higher prevalence of skin cancer than control group (Knobeloch et al., 2006). A significant dose-response relationship between arsenic concentrations and other tumors was also found in Taiwan, including bladder, kidney, and lung cancer in both sexes, and tumors of prostate and liver in males (Wu et al., 1989). The exact pathogenic mechanisms underlying inorganic arsenic exposure remain to be determined. Inorganic arsenic shows genotoxicity through several aspects, including chromosomal aberration (Oya-Ohta et al., 1996), genomic instability (Bhattacharjee et al., 2013) and p53 dysfunction (Hamadeh et al., 1999). Besides, the role of inorganic arsenic in epigenome has also been initially explored, including DNA methylation, microRNA, and histone modification. The methylation of CpG dinucleotides at the 5′ position on the pyrimidine ring forms 5-methylcytosine (5mC). This 5mC can alter transcription by blocking the binding of transcription factors and attracting methyl-binding proteins that initiate chromatin compaction for gene silencing (Li et al., 2015; Lunnon and Mill, 2013). Therefore, hypermethylation may result in gene silencing, while de-methylation may lead to gene activation (Tellez-Plaza et al., 2014). S-adenosyl-methionine (SAM), the substrate of DNA methyltransferases, is essential for methylation of inorganic arsenic to detoxication, and arsenic exposure was associated with hypomethylation of DNA and facilitates oncogenes expression (Zhao et al., 1997). Besides, hypermethylation of p53 and p16 promoters were found in people exposed to arsenic. On the other hand, histone modification (including histone acetylation and methylation), a covalent post-translational modification, plays an integral role in gene transcription (Allfrey and Mirsky, 1964; Dai, 2014). Intriguingly, previous report demonstrated that chronic arsenite exposure decreased H4K16ac in UROtsa cells (Jo et al., 2009). However, systematic characterizations to identify effector histone acetyltransferases and altered genomic loci with reduced histone acetylations remain to be done.