Evaluation of KCNMA1 as a biomarker and therapeutic target in colorectal cancer

KCNMA1 is a gene located at 10q22,that encodes for the pore-forming α-subunit of the large-conductance Ca2+-activated K+ channel.Growing evidence supports that K+ channels may be involved in oncogenesis. Amplification of the KCNMA1 gene was observed in 16% of advanced prostate tumors and an upregulation of its expression is observed in breast carcinoma and glioblastoma. In contrast, KCNMA1 is downregulated in primary cells and in gastric carcinoma cell lines, through hypermethylation of its promoter. In the present study, we have evaluated the expression levels of KCNMA1 both in a mouse model of colorectal cancer (CRC) and in human CRC samples and we have investigated the epigenetic mechanisms of its regulation. We observed a significant downregulation of KCNMA1 both in human and in mouse model of CRC. No differences in KCNMA1 levels were observed at different TNM stages and an inverse correlation was observed between KCNMA1 expression and overall survival of CRC patients. We also showed that the downregulation of KCNMA1 is associated to an increase in miR-17-5p and miR-31levels, as well as to an hypermetylationof the cg24113782 and cg25655799 loci of the promoter. Accordingly, treatment of the CRC cancer cell line, HT29, with the hypomethylating agent, Decitabine, increased KCNMA1 expression. Overall, our data suggest the possible use of KCNMA1 as a biomarker and/or prognostic factor in the early stages of colorectal cancer and as a possible therapeutic target.