m6A甲基转移酶METTL3的转录后修饰调节ERK诱导的脱氢酮抑制治疗耐药性前列腺癌。
Post-transcriptional modification of m6A methylase METTL3 regulates ERK-induced androgen-deprived treatment resistance prostate cancer.
发表日期：2023 Apr 24
作者：
Yang Li, Shimiao Zhu, Yutong Chen, Qianwang Ma, Duo Kan, Wenyue Yu, Boya Zhang, Xuanrong Chen, Wanqing Wei, Yi Shao, Keruo Wang, Mingpeng Zhang, Shu Deng, Yuanjie Niu, Zhiqun Shang
来源：
Cell Death & Disease
摘要：
作为RNA最常见的修饰形式，N6-甲基腺苷（m6A）已经确认参与了各种癌症的发生和发展。然而，m6A与去势抵抗性前列腺癌（CRPC）之间的关系还没有得到充分研究。通过对患者癌组织进行m6A测序，我们发现CRPC中的总m6A水平比去势敏感型前列腺癌（CSPC）高。根据m6A测序数据分析，我们发现HRas原癌基因、GTP酶（HRAS）和有丝分裂原激活蛋白激酶激酶2（MEK2或MAP2K2）的m6A修饰水平在CRPC中有所提高。具体来说，组织微阵列分析和分子生物学实验证实，去势后m6A“写入器”METTL3的表达上调，通过激活ERK途径促进腺激素剥夺治疗（ADT）抗性、细胞增殖和侵袭等恶性表型。我们揭示了METTL3介导ERK磷酸化是通过稳定HRAS的转录和正调节MEK2的翻译来实现的。在本研究建立的耐恩扎鲁胺抗性（Enz-R）C4-2和LNCap细胞系（C4-2R、LNCapR）中，我们确认ERK途径受METTL3调节。我们还发现，利用反义寡核苷酸（ASO）靶向METTL3/ERK轴可以在体外和体内恢复Enzalutamide的耐药性。总之，METTL3通过调节ERK途径的重要基因转录的m6A水平，激活ERK途径，并诱导Enzalutamide抵抗性。©2023年作者。
As the most common modification of RNA, N6-methyladenosin (m6A) has been confirmed to be involved in the occurrence and development of various cancers. However, the relationship between m6A and castration resistance prostate cancer (CRPC), has not been fully studied. By m6A-sequencing of patient cancer tissues, we identified that the overall level of m6A in CRPC was up-regulated than castration sensitive prostate cancer (CSPC). Based on the analysis of m6A-sequencing data, we found m6A modification level of HRas proto-oncogene, GTPase (HRAS) and mitogen-activated protein kinase kinase 2 (MEK2 or MAP2K2) were enhanced in CRPC. Specifically, tissue microarray analysis and molecular biology experiments confirmed that METTL3, an m6A "writer" up-regulated after castration, activated the ERK pathway to contribute to malignant phenotype including ADT resistance, cell proliferation and invasion. We revealed that METTL3-mediated ERK phosphorylation by stabilizing the transcription of HRAS and positively regulating the translation of MEK2. In the Enzalutamide-resistant (Enz-R) C4-2 and LNCap cell line (C4-2R, LNCapR) established in the current study, the ERK pathway was confirmed to be regulated by METTL3. We also found that applying antisense oligonucleotides (ASOs) to target the METTL3/ERK axis can restore Enzalutamide resistance in vitro and in vivo. In conclusion, METTL3 activated the ERK pathway and induced the resistance to Enzalutamide by regulating the m6A level of critical gene transcription in the ERK pathway.© 2023. The Author(s).