OPCML is frequently methylated in human colorectal cancer and its restored expression reverses EMT via downregulation of smad signaling.

Emerging evidence has indicated that the expression of OPCML gene is frequently altered in a variety of cancers. We previously demonstrated that the OPCML gene is a target of epigenetic inactivation and its gene product exhibits tumor-suppressive properties. However, little is known regarding the effects and mechanisms of OPCML in colon cancer. We show that the loss or downregulation of OPCML is associated with its promoter hypermethylation. Methylation of the OPCML promoter was detected in all tumors and tumor-adjacent tissues, but lower methylation in normal colon tissues. The drug-induced release of epigenetic silencing was able to restore OPCML expression and the re-expression led to the suppression of cell growth. Furthermore, the increase in OPCML expression reversed a partial epithelial-to-mesenchymal (EMT)-like transition. Cell migration and invasiveness were also inhibited in response to OPCML upregulation. These actions were mediated through the inactivation of TGFβ-Smad signaling pathways. In addition, OPCML expression was associated with two upstream nuclear receptors (ERRa and RORa). Altogether, our study reveals OPCML as a potential tumor suppressor gene epigenetically silenced in colon cancer. Our study will help to elucidate the anti-invasive mechanisms of OPCML and establish new chemotherapeutic strategies for human colon cancer.