Epigenetic regulation of MDR1 gene through post-translational histone modifications in prostate cancer

Abstract

BackgroundMultidrug resistance 1 (MDR1) gene encodes for an ATP binding cassette transporter - P-glycoprotein (P-gp) - involved in chemoresistance to taxanes. MDR1 promoter methylation is frequent in prostate carcinoma (PCa), suggesting an epigenetic regulation but no functional correlation has been established. We aimed to elucidate the epigenetic mechanisms involved in MDR1 deregulation in PCa.ResultsMDR1 promoter methylation and P-gp expression were assessed in 121 PCa, 39 high-grade prostatic intraepithelial neoplasia (HGPIN), 28 benign prostatic hyperplasia (BPH) and 10 morphologically normal prostate tissue (NPT) samples, using quantitative methylation specific PCR and immunohistochemistry, respectively. PCa cell lines were exposed to a DNA methyltransferases inhibitor 5-aza-2′deoxycytidine (DAC) and histone deacetylases inhibitor trichostatin A (TSA). Methylation and histone posttranscriptional modifications status were characterized and correlated with mRNA and protein expression. MDR1 promoter methylation levels and frequency significantly increased from NPTs, to HGPIN and to PCa. Conversely, decreased or absent P-gp immunoexpression was observed in HGPIN and PCa, inversely correlating with methylation levels. Exposure to DAC alone did not alter significantly methylation levels, although increased expression was apparent. However, P-gp mRNA and protein re-expression were higher in cell lines exposed to TSA alone or combined with DAC. Accordingly, histone active marks H3Ac, H3K4me2, H3K4me3, H3K9Ac, and H4Ac were increased at the MDR1 promoter after exposure to TSA alone or combined with DAC.ConclusionOur data suggests that, in prostate carcinogenesis, MDR1 downregulation is mainly due to histone post-translational modifications. This occurs concomitantly with aberrant promoter methylation, substantiating the association with P-gp decreased expression.

MDR1 mediated chemoresistance: BMI1 and TIP60 in action

“…The mechanisms proposed for chemotherapy-mediated upregulation of MDR1 also include mutational selection, aberrant signaling, e.g., Wnt/β-catenin and impaired p53, epigenetic changes involving histone methylation or acetylation and altered chromatin structure [14, 15, 20, 42, 66–69]. Since BMI1 itself is a transcriptional target of activated β-catenin, thus regulation of MDR1 expression by β-catenin knockdown might still involve BMI1 [70–72], however, we have ruled out any role for p53 in our system.…”

Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study

“…P-glycoprotein gene expression and protein production are controlled at several discrete points in the regulatory pathways leading from DNA to expression of functional protein, with final protein levels a function of translational and post-translational/epigenetic control. P-gp expression is under the control of transcription factors (Chen and Sikic, 2012;Henrique et al, 2013;Kobori et al, 2014) that can be activated by a wide variety of agents (Cascorbi, 2011). Expression is also altered epigenetically through changes in DNA methylation or acetylation (Reed et al, 2010;Chen and Sikic, 2012;Tomiyasu et al, 2014) or changes in ubiquitination (Zhang et al, 2004;Nawa et al, 2012).…”

Aberrant promoter methylation of the cadherin 13 gene in serum and its relationship with clinicopathological features of prostate cancer

“…6,7 DNA methylation can be detected not only in tumour samples but also in various body fluids such as blood, serum or plasma. 4,5 It is well known that DNA fragments are frequently and abundantly found in the serum of cancer patients (including patients with prostate cancer), and the detection of circulating tumourrelated methylated DNA may be used as a potential biomarker for the diagnosis, surveillance and prognosis of patients with prostate cancer.…”