Abstract
Human intestinal peptide transporter PEPT1 is commonly repressed in human colorectal cancer (CRC), yet its relationship with sensitivity to the common CRC treatment ubenimex has not previously been elucidated. In this study, we confirmed PEPT1 suppression in CRC using real-time quantitative polymerase chain reaction and western blotting and then investigated the underlying epigenetic pathways involved using bisulfite sequencing, chromatin immunoprecipitation, siRNA knockdown, and reporter gene assays. We found that PEPT1 transcriptional repression was due to both DNMT1-mediated DNA methylation of the proximal promoter region and HDAC1-mediated histone deacetylation, which blocked P300-mediated H3K18/27Ac at the PEPT1 distal promoter. Finally, the effects of the epigenetic activation of PEPT1 on the CRC response to ubenimex were evaluated using sequential combination therapy of decitabine and ubenimex both in vitro and in xenografts. In conclusion, epigenetic silencing of PEPT1 due to increased DNMT1 and HDAC1 expression plays a vital role in the poor response of CRC to ubenimex.
Highlights
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second most deadly cancer worldwide, with an estimated over 1.9 million new cases and 935,000 deaths recorded in 20201
Our results indicate that DNMT1 is associated with transcriptional repression of PEPT1 in CRC cells
Using The Cancer Genome Atlas (TCGA) analysis, we found that promoter methylation of PEPT1 is significantly increased in CRC tissues compared to normal tissues (Fig. 3B)
Summary
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second most deadly cancer worldwide, with an estimated over 1.9 million new cases and 935,000 deaths recorded in 20201. The diagnosis rates of advanced CRC with low overall survival (OS) remain high[1]. It is essential to identify novel biomarkers for the treatment, diagnosis, and prognosis of CRC. Chemotherapy is the treatment of choice to increase the OS of patients with. PEPT1 is predominantly responsible for the absorption of di/tripeptides and is mainly located on brush border membranes of small intestinal epithelia. In addition to that in the intestine, PEPT1 has been detected in tissues such as the nasal epithelium, kidney, biliary duct, and macrophages[7,8]. PEPT1 is overexpressed in the colon of inflammatory bowel disease patients and prostate cancer cells, which provides novel insight into the pathogenesis and tumor-specific drug delivery of this diseases[9,10]
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