Wild-Type IDH1 and Mutant IDH1 Opposingly Regulate Podoplanin Expression in Glioma

Chao Sun; Liming Xiao; Yuanlin Zhao; Jiankuan Shi; Yuan Yuan; Yu Gu; Feng Zhang; Xing Gao; Ying Yang; Risheng Yang; Junhui Qin; Jin Zhang; Chao Wang; Yingmei Wang; Zhe Wang; Peizhen Hu; Ting Chang; Liang Wang; Gang Wang; Huangtao Chen; Zhuyi Li; Jing Ye

doi:10.1016/j.tranon.2020.100758

Wild-Type IDH1 and Mutant IDH1 Opposingly Regulate Podoplanin Expression in Glioma

Transl Oncol. 2020 Apr;13(4):100758. doi: 10.1016/j.tranon.2020.100758. Epub 2020 Mar 21.

Authors

Chao Sun¹, Liming Xiao², Yuanlin Zhao², Jiankuan Shi³, Yuan Yuan², Yu Gu², Feng Zhang², Xing Gao², Ying Yang², Risheng Yang², Junhui Qin², Jin Zhang², Chao Wang⁴, Yingmei Wang², Zhe Wang², Peizhen Hu², Ting Chang⁵, Liang Wang⁶, Gang Wang⁷, Huangtao Chen⁸, Zhuyi Li⁹, Jing Ye¹⁰

Affiliations

¹ State Key Laboratory of Cancer Biology and Department of Pathology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China, 710032; Department of Neurology, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China, 710032.
² State Key Laboratory of Cancer Biology and Department of Pathology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China, 710032.
³ State Key Laboratory of Cancer Biology and Department of Pathology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China, 710032; Department of Neurology, International Medical Center Hospital, Xi'an, China, 710100.
⁴ Department of Pathology, Chengdu Military General Hospital, Chengdu, China, 610083.
⁵ Department of Neurology, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China, 710032.
⁶ Department of Neurosurgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China, 710032.
⁷ Department of General Surgery, the 74th Group Army Hospital, Guangzhou, China, 510318.
⁸ Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, China, 710061.
⁹ Department of Neurology, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China, 710032. Electronic address: lizhuyi@fmmu.edu.cn.
¹⁰ State Key Laboratory of Cancer Biology and Department of Pathology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China, 710032; Department of Neurology, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China, 710032. Electronic address: yejing@fmmu.edu.cn.

Abstract

Isocitrate dehydrogenase (IDH) mutations occur frequently in lower-grade gliomas, which result in genome-wide epigenetic alterations. The wild-type IDH1 is reported to participate in lipid biosynthesis and amino acid metabolism, but its role in tumorigenesis is still unclear. In this study, the expressions of IDH1 and podoplanin (Pdpn) were determined in IDH-mutated and IDH-wild-type gliomas, and their relationships in glioma were further analyzed. In addition, the regulation of wild-type IDH1 and mutant IDH1 on Pdpn expression was investigated by luciferase assays and promoter methylation analysis. Our study showed that Pdpn was almost undetectable in IDH-mutated glioma but strongly expressed in higher-grade IDH-wild-type glioma. Pdpn overexpression promoted the migration of glioma cells but had little effect on cell growth. Moreover, Pdpn expression was positively correlated with the increased wild-type IDH1 levels in IDH-wild-type glioma. Consistently, the wild-type IDH1 greatly promoted the transcription and expression of Pdpn, but the mutant IDH1 and D-2-hydroxyglutarate significantly suppressed Pdpn expression in glioma cells. Besides, our results revealed that the methylation of CpG islands in the Pdpn promoter was opposingly regulated by wild-type and mutant IDH1 in glioma. Collectively, our results indicated that wild-type and mutant IDH1 opposingly controlled the Pdpn expression in glioma by regulating its promoter methylation, which provides a basis for understanding the relationship between wild-type and mutant IDH1 in epigenetic regulation and tumorigenesis.