Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. It develops in a complex multi-step process. The majority of studies to date have focused on genetic mutations and epigenetic changes that drive the CRC carcinogenesis process. Xenobiotic transporters play an important role in safeguarding our body from external toxic substances. These transporters lining the gastrointestinal tract may thus protect us from the dietary carcinogens. This study aims to investigate the downregulation of an efflux transporter ABCG2 in colorectal cancer versus normal colon mucosa, so as to shed some light on its relevance to CRC initiation and progression. We found that ABCG2 expression is at least 50-fold lower in adenomatous polyps and colon carcinoma specimens obtained from CRC patients than in their matched pair of adjacent normal colon mucosa. This may facilitate the accumulation of genotoxins to propel tumor initiation and progression. The underlying mechanism(s) for ABCG2 under-expression in CRC is currently not known. To this end, aberrant promoter methylation of ABCG2 has been reported to cause its repression in a few cancer types including renal carcinoma and multiple myeloma. On the other hand, ABCG2 promoter demethylation has been reported to upregulate the transporter to mediate multidrug resistance in lung cancer and acute lymphoblastic leukemia. In this study, miR-203 was found to be downregulated in all polyps and CRC specimens, relative to adjacent normal colon mucosa. We demonstrated that the de novo DNA methyltransferase DNMT3 is a direct target of miR-203. Importantly, by relieving the repression on DNMT3, the lower expression of miR-203 in CRC caused remarkable ABCG2 promoter methylation and lower ABCG2 expression in colon cancer cell lines and the patient CRC specimens. In spite of the complex sequential genetic mutations and epigenetic changes leading to CRC formation, we proposed that the restoration of the xenobiotic transporter ABCG2 function via modulating this new microRNA-DNA methylation mechanism in precancerous cells may represent an attractive strategy to stop or delay the carcinogenesis process.

Citation Format: Kenneth K.W. To, Wing Wah Leung, Simon S.M. Ng. Epigenetic downregulation of ABCG2 in colorectal cancer by a novel microRNA-DNA methylation mechanism - an attractive target for cancer prevention. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-292. doi:10.1158/1538-7445.AM2015-LB-292