Our extensive preliminary data suggest that the loss

Our extensive preliminary data suggest that the loss of p300 (and resulting H3K27ac) is related to inorganic arsenic related diseases. Therefore, it may open a new avenue for alleviating the consequence of H3K27ac, for example, via boosting CBP enzymatic activity for at least partially compensating p300 functions (Iyer et al., 2004; Kasper et al., 2006). It is known that EP300 and its regulated gene Kif4 (silenced after arsenic exposure; C) are tumor suppressors (Iyer et al., 2004). For example, p300 works as a tumor suppressor in hematological tumors (Kung et al., 2000; Oike et al., 1999). Down-expression of p53 and p300 were also found in azoxymethane treated mice, which is a colon-specific carcinogen (Aizu et al., 2003). The role of Klf4 as a tumor suppressor has been validated in colorectal cancer (Zhao et al., 2004), non-Hodgkin lymphoma (Guan et al., 2010), classic Hodgkin lymphoma (Guan et al., 2010), and pancreatic ductal carcinoma (Zammarchi et al., 2011). According to our results, it is reasonable to speculate that As induced p300 downregulation, and decreased Klf4 may promote the Remodelin australia of tumors. Other researchers also reported this result (Evans et al., 2007). In conclusion, for the first time, we reported that sodium arsenite inhibited EP300 at both mRNA and protein levels, which led to the decreased H3K27ac signals. Future experiments to confirm a similar mechanism in the long-term exposed mouse would be significant for arsenic-caused human health problems.
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Acknowledgment The laboratory of Z.W was supported by National Institutes of Health, United States (R01ES25761, U01ES026721 opportunity fund, and R21ES028351) and Johns Hopkins Catalyst Award. Q.Z thanks China Scholarship Council, China and the National Natural Science Foundation of China (81302390) for support. This work was also made possible by the ChuTian Professorship from Hubei University, China and support from GENEWIZ Suzhou. Lastly, extensive bioinformatic analyses were possible only with computational resources (and/or scientific computing services) at the Maryland Advanced Research Computing Center (MARCC). We are therefore greatly indebted to the support from MARCC.
Introduction Colorectal cancer (CRC) is the third more common malignant neoplasm worldwide and the second leading cause of cancer deaths in developed countries [1]. Although adjuvant or palliative chemotherapy based on 5-Fluorouracil (5-FU) is an essential treatment for the majority of CRC patients [2], [3], the response rate of current treatment regimens remains discouragingly low (10–15% with 5-FU alone and less than 50% when 5-FU is combined with other cytotoxic drugs) [4], [5]. An underlying resistance to 5-FU chemotherapy, including intrinsic and acquired resistance, remains a leading cause for treatment failure [6]. Moreover, current biomarkers for predicting therapeutic efficacy following 5-FU treatment possess their own limitations in clinical practice [7], [8]. An improved understanding of the mechanisms underlying the anti-neoplastic properties of 5-FU is required to better predict and improve the clinical response to 5-FU. 5-FU is known to be metabolized like uracil to interfere with the metabolism of nucleic acids [4]. The metabolite fluorodeoxyuridine monophosphate also inhibits the activity of thymidylate synthase, a critical enzyme of nucleotide synthesis, to shut off DNA synthesis [9]. However, these findings cannot fully explain the complex anti-neoplastic effects of 5-FU, or allow us to accurately predict the clinical response to 5-FU treatment. In addition to blocking nucleic acid metabolism, 5-FU possesses a myriad of biological activities, including the ability to recode histone modifications [10]. Histone modification, especially histone acetylation, is important in establishing chromatin environments and regulating gene expression [11]. Moreover, histone modification is closely associated with therapeutic sensitivity of tumors [12], [13], which makes it a well-established anti-cancer target [14]. For example, many studies have demonstrated over-increasing histone acetylation may reverse 5-FU resistance and potentially improve therapeutic outcome in CRC [15], [16]. Therefore, a better understanding of the 5-FU histone-modifying effects is helpful to reveal the mechanism of 5-FU resistance. Many factors such as oxidative stress, DNA damage or some artificial compounds may influence histone acetylation in cancer cells by working on histone acetyltransferases (HATs) or histone deacetylases (HDACs) [17], [18]. It therefore is possible that 5-FU affects histone acetylation either by altering the amount of histone-modifying enzymes or by influencing their catalytic activity. Besides the possibility that 5-FU may inhibit the synthesis of histone-modifying enzymes, it remains possible that 5-FU promotes their degradation, since 5-FU has been shown to induce extensive protein degradation by activating autophagy in cancer cells [19]. Autophagy is a beneficial protein-degradation system for cells to maintain cellular metabolism under starvation or stress, which is also relevant to cellular resistance to cytotoxic drugs in cancer [20], [21].