SDHx突变影响TET糖基化及其诱发嗜铬细胞瘤的分子机制研究

最新研究发现，SDHx突变嗜铬细胞瘤（PCC）的发生主要是由于DNA去甲基化酶TET活性抑制引发关键抑癌基因关闭，然而TET通过何种机制以及关闭了何种抑癌基因尚不清楚。我们前期在PCC中发现了受DNA甲基化精确调节的新抑癌基因PCCRP，其在SDHx突变的PCC中由于启动子高甲基化而关闭，并通过MAPK-pErK1/2信号通路影响嗜铬细胞增殖。本项目通过对比不同遗传背景的PCC，筛选SDHx突变PCC中活性与定位发生变化的TET分子；并构建SDH失活细胞系，通过分子生物学手段分析SDH失活对TET糖基化的影响以及糖基化TET的活性与稳定性变化，建立TET与PCCRP高甲基化的关系，寻找SDH失活通过影响TET糖基化从而造成PCCRP关闭并引发PCC的证据。本项目旨在阐明SDH失活与PCC发生的潜在关系，探究糖基化修饰影响TET活性的相关机制，为PCC临床诊断和治疗提供新思路与理论指导。

SDHx mutation causes pheochromocytoma (PCC) in special way, which is different from other susceptiblity genes. PCC with SDHx mutation mainly results from TET activity suppression and subsequent key tumor suppressor genes shutting down. However, the accurate machanism mediated by TET is not clear. We previously found PCCRP as a novel epigentic tumor suppessor in sporadic PCC. The PCCRP expression is down-reglulated in PCC with SDHx mutation due to high methylation of CpG island and it inhibits chromaffin cell proliferation via blocking MAPK-pErK1/2 pathway. In this project, we are going to screen the functional molecues in TET family and analyze the effects of SDH inactivtion on TET O-GlcNAcylation and protein stablity, and established the relationship between TET activity and PCCRP methylation. Furthermore, we will search for the evidence about PCC with PCCRP high methylation pheotype caused by SDH inactivation impacting on TET O-GlcNAcylation, maybe revealing a novel mechanism of PCC development. Our project aims to confirm the potential connection between SDH inactivtion and PCC and replenish the information about the effect of O-GlcNAcylation on TET actitity, providing new ideas and theoretical guidance for clinical diagnosis and treatment of PCC.