Aberrant Epigenetic Modifications of LPHN2 Function as a Potential Cisplatin-Specific Biomarker for Human Gastrointestinal Cancer.
OBJECTIVE
Epigenetic alterations of specific genes have recently been identified as diagnostic biomarkers for human cancers. However, there are currently no standardized epigenetic biomarkers for drug sensitivity in human gastrointestinal cancer. Therefore, the aim of this study is to identify a novel epigenetic biomarker in gastrointestinal cancer.


METHODS
Using bisulfite sequencing and pyrosequencing analysis, DNA methylation patterns of gastric, colon primary tissues and their cancer cells were analyzed, and histone modifications were analyzed using chromatin immunoprecipitation assay. In addition, cancer cells were exposed to cisplatin and treated with a DNA methyltransferase inhibitor.


RESULTS
We report that in human gastric and colon cancers, latrophilin 2 (LPHN2) is silenced by epigenetic modifications, including CpG island methylation and aberrant histone modifications. We also confirmed that LPHN2 was silenced by DNA hypermethylation in primary gastric and colon tumor tissues compared to their normal counterparts. Interestingly, we found that cancer cells with methylated LPHN2 showed higher sensitivity to cisplatin. Also, 5-aza- 2'-deoxycytidine combined with cisplatin decreased the cytotoxicity of cisplatin in cancer cells with methylated LPHN2. In addition, LPHN2 knockdown in cancer cells with high LPHN2 expression sensitized these cells to the anti-proliferative effects of cisplatin.


CONCLUSIONS
In human gastrointestinal cancer, we found that LPHN2 is regulated by epigenetic modifications, and that cancer cells with lower LPHN2 expression show higher sensitivity to cisplatin. Therefore, the methylation status of LPHN2 is a potential novel epigenetic biomarker for cisplatin treatment in human gastric and colon cancers.
Cancer Research Institute, Seoul National University, Seoul, Korea.|Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.
Mi-Seong
MS
Jeon
Cancer Research Institute, Seoul National University, Seoul, Korea.
Sang-Hyun
SH
Song
Cancer Research Institute, Seoul National University, Seoul, Korea.|Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.
Jiyeon
J
Yun
Cancer Research Institute, Seoul National University, Seoul, Korea.|Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.
Jee-Youn
JY
Kang
Cancer Research Institute, Seoul National University, Seoul, Korea.
Hwang-Phill
HP
Kim
Cancer Research Institute, Seoul National University, Seoul, Korea.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
Sae-Won
SW
Han
Cancer Research Institute, Seoul National University, Seoul, Korea.|Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
Tae-You
TY
Kim
D015415:Biomarkers; D002945:Cisplatin / Q000627:therapeutic use*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*
C117618:ADGRL2 protein, human; D015415:Biomarkers; D043562:Receptors, G-Protein-Coupled; D002945:Cisplatin
Cisplatin; DNA methylation; Epigenomics; Histone modification; LPHN2