人类非整倍体细胞中RNA和蛋白质降解的增加是抵抗转录负荷和蛋白质毒性应激所必需的

Increased RNA and Protein Degradation Is Required for Counteracting Transcriptional Burden and Proteotoxic Stress in Human Aneuploid Cells

Cancer Discovery

影响因子:33.3

分区:医学1区 Top / 肿瘤学1区

发表日期:2024 Dec 02

作者: Marica Rosaria Ippolito, Johanna Zerbib, Yonatan Eliezer, Eli Reuveni, Sonia Viganò, Giuseppina De Feudis, Eldad D Shulman, Anouk Savir Kadmon, Rachel Slutsky, Tiangen Chang, Emma M Campagnolo, Silvia Taglietti, Simone Scorzoni, Sara Gianotti, Sara Martin, Julia Muenzner, Michael Mülleder, Nir Rozenblum, Carmela Rubolino, Tal Ben-Yishay, Kathrin Laue, Yael Cohen-Sharir, Ilaria Vigorito, Francesco Nicassio, Eytan Ruppin, Markus Ralser, Francisca Vazquez, Stefano Santaguida, Uri Ben-David

DOI: 10.1158/2159-8290.CD-23-0309

摘要

非整倍体导致蛋白质复合物的化学计量失衡，危及细胞适应性。因此，非整倍体细胞需要通过调节RNA和蛋白质水平来补偿DNA水平的不平衡，但其分子机制仍未完全阐明。本研究分析了多种二倍体与非整倍体细胞模型。发现非整倍体细胞通过增加多条RNA降解途径来应对转录负荷，因此对RNA降解的扰动更为敏感。在蛋白质水平上，非整倍体细胞通过减少蛋白质翻译和增加蛋白质降解来缓解蛋白质毒性应激，使其对蛋白酶体抑制剂更为敏感。这些发现通过数百个人类癌细胞系和原发性肿瘤得到了验证，且非整倍体水平与多发性骨髓瘤患者对蛋白酶体抑制剂的反应显著相关。因此，非整倍体细胞在基因表达过程中依赖多个关键节点，为其提供临床上可利用的潜在弱点。意义：非整倍体是癌症的标志，与预后不良和药物反应差相关。我们揭示了携带额外染色体的细胞通过改变RNA和蛋白质代谢来补偿DNA内容的失衡，从而对RNA和蛋白质降解的扰动更为敏感。

Abstract

Aneuploidy results in a stoichiometric imbalance of protein complexes that jeopardizes cellular fitness. Aneuploid cells thus need to compensate for the imbalanced DNA levels by regulating their RNA and protein levels, but the underlying molecular mechanisms remain unknown. In this study, we dissected multiple diploid versus aneuploid cell models. We found that aneuploid cells cope with transcriptional burden by increasing several RNA degradation pathways, and are consequently more sensitive to the perturbation of RNA degradation. At the protein level, aneuploid cells mitigate proteotoxic stress by reducing protein translation and increasing protein degradation, rendering them more sensitive to proteasome inhibition. These findings were recapitulated across hundreds of human cancer cell lines and primary tumors, and aneuploidy levels were significantly associated with the response of patients with multiple myeloma to proteasome inhibitors. Aneuploid cells are therefore preferentially dependent on several key nodes along the gene expression process, creating clinically actionable vulnerabilities in aneuploid cells. Significance: Aneuploidy is a hallmark of cancer that is associated with poor prognosis and worse drug response. We reveal that cells with extra chromosomes compensate for their imbalanced DNA content by altering their RNA and protein metabolism, rendering them more sensitive to perturbation of RNA and protein degradation. See related commentary by Bakhoum, p. 2315.