S-Space Graduate School of Convergence Science and Technology (융합과학기술대학원) Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과) Theses (Master's Degree_분자의학 및 바이오제약학과)
Aberrant epigenetic modifications of LPHN2 function as a potential cisplatin-specific biomarker for human gastrointestinal cancer
위장관암에서 Cisplatin에 특이적인 바이오마커로서 LPHN2의 비정상적인 후성유전학적 변이에 관한 연구
- Jeon Mi-Seong
- 융합과학기술대학원 분자의학 및 바이오제약학과
- Issue Date
- 서울대학교 융합과학기술대학원
- 후성유전학 ; DNA methylation ; histone modification ; 5-Aza-2’-deoxycytidine ; LPHN2 ; chemosensitivity
- 학위논문 (석사)-- 서울대학교 융합과학기술대학원 : 융합과학기술대학원 분자의학 및 바이오제약학과, 2016. 2. 김태유.
- 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.