Aberrant epigenetic modifications of LPHN2 function as a potential cisplatin-specific biomarker for human gastrointestinal cancer

Abstract

Epigenetic alterations, such as DNA methylation and histone modifications, are considered common mechanisms that contribute to aberrant gene expression during tumorigenesis. Recently, epigenetic alterations of specific genes have been identified as diagnostic biomarkers for human cancers. However, there are currently no standardized epigenetic biomarkers for drug sensitivity in human gastrointestinal cancer. Here I report that in human gastric and colon cancers, Latrophilin2 (LPHN2) is silenced by epigenetic modifications, including CpG island methylation and aberrant histone modifications. Treatment with a DNA methyltransferase inhibitor induced demethylation of the methylated LPHN2 CpG island and altered histone modifications around the LPHN2 promoter, thereby restoring LPHN2 expression. In addition, I confirmed that LPHN2 was silenced by DNA hypermethylation in primary gastric and colon tumor tissues compared to their normal counterparts. Interestingly, I found that cancer cells with methylated LPHN2 exhibited higher sensitivity to cisplatin. Also, 5-Aza-2′-deoxycytidine (5-aza-CdR) combined with cisplatin decreased the cytotoxicity of cisplatin in cancer cells with methylated LPHN2. Moreover, LPHN2 knockdown in cancer cells with high LPHN2 expression sensitized these cells to the anti-proliferative effects of cisplatin. Because the LPHN2 methylation status was not responsible for differential sensitivity to other chemotherapeutic drugs, the methylation status of LPHN2 might confer sensitivity to cisplatin in human gastric and colon cancers. Taken together, my data suggest that epigenetic alterations induce transcriptional inactivation of LPHN2, which intensifies the response to cisplatin in human gastric and colon cancers. Thus, the methylation status of LPHN2 is a potential novel epigenetic biomarker for cisplatin treatment in human gastric and colon cancers.