Calcium-sensing receptor silencing in colorectal cancer is associated with promoter hypermethylation and loss of acetylation on histone 3.
Fetahu IS, Höbaus J, Aggarwal A, Hummel DM, Tennakoon S, Mesteri I, Baumgartner-Parzer S, Kállay E. Int J Cancer. 2014 Nov 1;135(9):2014-23. doi: 10.1002/ijc.28856. Epub 2014 Apr 2.
The recently published article of Irfete Fetahu from the group Tumourpathology (led by E. Kallay) was selected as “Editors’ choice”. In this paper Dr. Fetahu describes mechanisms that can cause silencing of the calcium sensing receptor in colorectal tumours.
The calcium-sensing receptor (CaSR) is suggested to mediate the antiproliferative effects of calcium in colon. However, in colorectal cancer (CRC) the expression of the CaSR is silenced and the underlying mechanisms leading to its loss are poorly understood. In this paper Irfete Fetahu and her colleagues investigated whether loss of the CaSR expression in colorectal tumours is caused by DNA hypermethylation and imbalance of transcriptionally permissive/repressive histone alterations. The expression of the CaSR was significantly lower in colorectal tumours compared with the adjacent mucosa from the same patient both on mRNA and protein level. The promoter of the CaSR was methylated to a greater extent in tumours compared with the adjacent mucosa, and the methylation level correlated inversely with mRNA expression. The fact that DNA methylation is one cause of silencing CaSR expression was further proven by the fact that in some cell lines treatments with 5-aza-2′-deoxycytidine (DAC), a DNA methyltransferase inhibitor restored CaSR expression. Interestingly, demethylation of the DNA was not able to increase CaSR expression in all cell lines studied. In some cases acetylation of lysine 9 on histone 3 (H3K9) was also needed to restore CaSR expression. The restored CaSR in cancer cell lines was functional. Inhibition of lysine-specific demethylase 1 (LSD1) to prevent demethylation of mono- and dimethylated H3K4, increased CaSR expression only marginally. Our data show that hypermethylation of the CaSR promoter and H3K9 deacetylation, but not H3K4me2 demethylation are important factors that cause silencing of the CaSR in colorectal cancer.