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研究揭示ERα在维持肿瘤细胞存活和耐药中的新功能
作者:小柯机器人 发布时间:2021/9/24 15:04:30

美国加州大学Davide Ruggero小组的最新研究揭示,雌激素受体α(ERα)是维持肿瘤细胞存活和耐药的rna结合蛋白。2021年9月23日出版的《细胞》在线发表了这项成果。

在本研究中,研究人员发现ERα是一种有效的非经典RNA结合蛋白。研究表明 ERα的RNA结合功能与其结合DNA的活性分离,并且对乳腺癌的进展至关重要。采用全基因组交联免疫沉淀(CLIP)测序和功能性CRISPRi筛选,研究人员发现ERα相关mRNA维持癌细胞稳定并引发细胞对压力的反应。

从机制上讲,ERα控制 RNA代谢的不同步骤。特别是,研究证明ERα与RNA结合介导了XBP1的选择性剪接以及eIF4G2和MCL1 mRNA的翻译,这有助于在压力条件下癌细胞的存活并维持癌细胞对他莫昔芬的抗性。因此,ERα是一种多能RNA结合蛋白,这一活性改变了人类对癌症进展和药物反应转录后调控的认知。 

据了解,ERα是一种激素受体,是70%以上乳腺癌的关键诱发因素,几十年来人们一直把它作为转录因子展开研究。

附:英文原文

Title: ERα is an RNA-binding protein sustaining tumor cell survival and drug resistance

Author: Yichen Xu, Peiwei Huangyang, Ying Wang, Lingru Xue, Emily Devericks, Hao G. Nguyen, Xiuyan Yu, Juan A. Oses-Prieto, Alma L. Burlingame, Sohit Miglani, Hani Goodarzi, Davide Ruggero

Issue&Volume: 2021-09-23

Abstract: Estrogen receptor α (ERα) is a hormone receptor and key driver for over 70% of breastcancers that has been studied for decades as a transcription factor. Unexpectedly,we discover that ERα is a potent non-canonical RNA-binding protein. We show that ERαRNA binding function is uncoupled from its activity to bind DNA and critical for breastcancer progression. Employing genome-wide cross-linking immunoprecipitation (CLIP)sequencing and a functional CRISPRi screen, we find that ERα-associated mRNAs sustaincancer cell fitness and elicit cellular responses to stress. Mechanistically, ERαcontrols different steps of RNA metabolism. In particular, we demonstrate that ERαRNA binding mediates alternative splicing of XBP1 and translation of the eIF4G2 andMCL1 mRNAs, which facilitates survival upon stress conditions and sustains tamoxifenresistance of cancer cells. ERα is therefore a multifaceted RNA-binding protein, andthis activity transforms our knowledge of post-transcriptional regulation underlyingcancer development and drug response.

DOI: 10.1016/j.cell.2021.08.036

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01047-3

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/