Repositori institucional URV
| URV's Author/s: | Yanes Torrado, Óscar |
| Author, as appears in the article.: | Valentina Ramponi; Laia Richart; Marta Kovatcheva; Camille Stephan‐Otto Attolini; Jordi Capellades; Alice Lord; Óscar Yanes; Gabriella Ficz; Manuel Serrano |
| Author's mail: | oscar.yanes@urv.cat |
| Author identifier: | 0000-0003-3695-7157 |
| Journal publication year: | 2024 |
| Publication Type: | Journal Publications |
| APA: | Valentina Ramponi; Laia Richart; Marta Kovatcheva; Camille Stephan‐Otto Attolini; Jordi Capellades; Alice Lord; Óscar Yanes; Gabriella Ficz; Manuel Se (2024). H4K20me3-Mediated Repression of Inflammatory Genes is a Characteristic and Targetable Vulnerability of Persister Cancer Cells.. Cancer Research, (), -. DOI: 10.1158/0008-5472.CAN-24-0529 |
| Papper original source: | Cancer Research. |
| Abstract: | Anti-cancer therapies can induce cellular senescence, which is highly stable, or drug-tolerant persistence, which is efficiently reversed upon therapy termination. While approaches to target senescent cells have been extensively studied, further understanding of the processes regulating persistence is needed to develop treatment strategies to suppress persister cell survival. Here, we used mTOR/PI3K inhibition to develop and characterize a model of persistence-associated arrest in human cancer cells of various origins. Persister and senescent cancer cells shared an expanded lysosomal compartment and hypersensitivity to BCL-XL inhibition. However, persister cells lacked other features of senescence, such as loss of lamin B1, senescence-associated β-galactosidase activity, upregulation of MHC-I, and an inflammatory and secretory phenotype (SASP). Genome-wide CRISPR/Cas9 screening for genes required for the survival of persister cells revealed that they are hypersensitive to the inhibition of one-carbon (1C) metabolism, which was validated by the pharmacological inhibition of SHMT, a key enzyme that feeds methyl groups from serine into 1C metabolism. Connecting 1C metabolism with the epigenetic regulation of transcription, the repressive heterochromatic mark H4K20me3 was enriched at the promoters of SASP and interferon response genes in persister cells, while it was absent in proliferative or senescent cells. Moreover, persister cells overexpressed the H4K20 methyltransferases KMT5B/C, and their downregulation unleashed inflammatory programs and compromised the survival of persister cells. In summary, this study defined distinctive features of persister cancer cells, identified actionable vulnerabilities, and provided mechanistic insight into their low inflammatory activity. |
| Article's DOI: | 10.1158/0008-5472.CAN-24-0529 |
| Link to the original source: | https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-24-0529/749582/H4K20me3-Mediated-Repression-of-Inflammatory-Genes |
| Papper version: | info:eu-repo/semantics/publishedVersion |
| licence for use: | https://creativecommons.org/licenses/by/3.0/es/ |
| Department: | Enginyeria Electrònica, Elèctrica i Automàtica |
| Licence document URL: | https://repositori.urv.cat/ca/proteccio-de-dades/ |
| Thematic Areas: | Astronomia / física Biotecnología Cancer research Ciências biológicas i Ciências biológicas ii Ciências biológicas iii Farmacia General medicine Interdisciplinar Medicina i Medicina ii Medicina iii Medicina veterinaria Odontología Oncology Química Saúde coletiva |
| Keywords: | Good health and well-being |
| Entity: | Universitat Rovira i Virgili |
| Record's date: | 2024-11-23 |
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