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

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.

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Publication Details

Journal
Cancer Discovery
Published
2024-09-09
DOI
https://doi.org/10.1158/2159-8290.cd-23-0309
Citations
29
Primary Topic
Microtubule and mitosis dynamics
Type
article
Field-Weighted Citation Impact
9.13

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article

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

Johanna Zerbib, Giuseppina De Feudis, Carmela Rubolino, Ilaria Vigorito et al.
29 citations
Cancer Discovery
Microtubule and mitosis dynamics
9.13
article

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

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

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.

Cancer DiscoveryVol. 14(12)
Broad Institute (US), National Institutes of Health (US), Tel Aviv University (IL), University of Milan (IT), Nuffield Orthopaedic Centre (GB), Italian Institute of Technology (IT), University of Oxford (GB), Centro Cardiologico Monzino (IT), Exact Sciences (United States) (US), National Cancer Institute (US), Max Planck Institute for Molecular Genetics (DE), Center for Genomic Science (IT), High Throughput Biology (United States) (US), European Institute of Oncology (IT), Charité - Universitätsmedizin Berlin (DE)
Israel Cancer Research Fund, Bristol-Myers Squibb, Pfizer, Novocure, Broad Institute, Fondazione Cariplo, Ministero della Salute, Ministero dell’Istruzione, dell’Università e della Ricerca, Associazione Italiana per la Ricerca sul Cancro, Azrieli Foundation, Congressionally Directed Medical Research Programs
Good health and well-being
Openalex Percentile: Top 1%
Microtubule and mitosis dynamics
9.13
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