| Colorectal cancer(CRC),as one of the most common malignancies of the digestive tract,ranked the third and second in the highest incidence and mortality rates of all malignancies worldwide,respectively.In China,the number of new CRC cases and CRCrelated deaths also have been increasing annually and the incidence in younger adults(age <50 years)unexpectedly increased.Additionally,although CRC incidence and mortality have declined globally due to advanced screening and therapeutic programs,the diagnosis rates of advanced CRC with low overall survival(OS)remain high and therapy is limited.Therefore,it’s necessary and important to develop new effective therapy to expand or even refine existing CRC therapy.Epigenetics,defined as heritable alterations in gene expression that do not change the DNA sequence,has a central role in the initiation,progression,and metastasis of various cancer,including CRC.The study of DNA methylation,histone modifications,non-coding RNAs as well as RNA methylation has unequivocally illustrated the missing link between certain specific gene expression patterns and the absence of genetic alterations in CRC over the past two decades.DNA methylation and mi RNAs have been identified as excellent and potential biomarkers of clinical translation for diagnosis,prognosis,and prediction of treatment response in CRC,some DNA methylation biomarkers have been commercialized and used in current clinical practice,or even in clinical guidelines for CRC,for example the methylation of SEPT9.Histone modifications are less appealing to be recongnized as biomarker due to their complex interactions with genes and the technical limitations of quantitative analysis,as well as the lack of specificity for different cancers.The research on the RNA methylation in CRC is still on the way.In summary,focusing on the epigenetic modifications in CRC has not only improved our understanding of CRC pathophysiology but also opened the door to discover new disease biomarkers and therapeutic targets.Nowadays,chemotherapy is still the dominant adjuvant therapy to increase the OS of patients with advanced or metastatic CRC.The resistance of malignant tumor cells to chemotherapy is a crucial reason for poor survival among CRC patients.One explanation for this multidrug resistance(MDR)to cancer chemotherapy is that the increased efflux and reduced influx of chemotherapy drugs mediated by drug transporters are responsible.The peptide transporter PEPT1(encoded by SLC15A1)is expressed predominantly in the brush-border membrane of the intestine and also can be detected in the kidney and bile duct.PEPT1 mediates the absorption of dietary nutrients(di/tripeptide)or peptidomimetic drugs,including β-lactam antibiotics such as cephalosporin,angiotensin converting enzyme(ACE)inhibitors such as captopril,anticancer agents such as ubenimex,and antiviral therapeutics such as valacyclovir.From these perspective,we speculated that the expression of PEPT1 is associated with the anti-tumor efficacy of ubenimex in CRC.In this study,we confirmed the PEPT1 suppression in CRC by real-time quantitative polymerase chain reaction and western blotting and then investigated the underlying epigenetic modifications including DNA methylation and histone acetylation through bisulfite sequencing,chromatin immunoprecipitation,si RNA knockdown,and reporter gene assays.We found that PEPT1 transcriptional repression was introduced by both the DNMT1-mediated DNA methylation of its proximal promoter region and HDAC1-mediated histone deacetylation,which blocked P300-mediated H3K18/27 Ac at the PEPT1 distal promoter.Finally,the effects of the epigenetic activation of PEPT1 over 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. |
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