去甲基化酶JMJD6通过调控自噬和凋亡来影响BRAF突变型黑色素瘤耐药性的机制研究

黑色素瘤是发病率和致死率最高的皮肤性原发恶性肿瘤，其中50%携带原癌基因BRAF突变。MEK和BRAF抑制剂联用是BRAF突变型黑色素瘤的主要治疗方法，但已经出现一定耐药性和副作用。耐药性产生可能与PI3K/Akt/mTOR介导的凋亡失控和ERK重新激活介导的自噬保护有关，但具体协调两者的分子机制尚不明确。目前研究表明去甲基化酶JMJD6可以上调包括ERK、MYC和Akt在内的原癌基因转录水平，并且在耐药型黑色素瘤中高表达。本项目拟首先研究JMJD6及其相关通路诱导BRAF突变型黑色素瘤耐药性形成机制；其次明确JMJD6介导的自噬发生和凋亡功能障碍对BRAF突变型黑色素瘤耐药性形成的可能作用；最后探究靶向JMJD6及其相关通路是否能改善耐药BRAF突变型黑色素瘤的药物敏感性。总之，本项目旨在阐述BRAF突变型黑色素瘤耐药性产生的分子机制，同时为现阶段临床药物治疗肿瘤提供新靶点。

Melanoma is the primary malignant tumor of the skin with the highest morbidity and fatality, of which 50% carry proto-oncogene BRAF-mutation. The combination of MEK and BRAF inhibitors is the main treatment of BRAF-mutant melanoma, but there have been some drug resistance and side effects. The occurrence of drug resistance may be related to uncontrolled apoptosis mediated by PI3K/Akt/mTOR and autophagy protection mediated by ERK reactivation, but the specific molecular mechanism is not clear. Recent studies have shown that the demethylase JMJD6 could up-regulate the transcription of proto-oncogenes including ERK, MYC and Akt, along with high levels of expression in drug-resistant melanoma. The purpose of this project is to firstly study the mechanism of drug resistance in BRAF-mutant melanoma induced by JMJD6 and its related pathways; secondly, to clarify the possible role of JMJD6-mediated autophagy and apoptosis dysfunction in the formation of drug resistance in BRAF- mutant melanoma; finally, to explore whether targeted JMJD6 and its related pathways can improve the drug sensitivity of drug-resistant BRAF-mutant melanoma. In summary, the purpose of this project is to explain the molecular mechanism of drug resistance in BRAF-mutant melanoma and to provide a new target for clinical drug therapy at the present stage.