Products Cited in Publications Worldwide H4K20me3-Mediated Repression of Inflammatory Genes is a Characteristic and Targetable Vulnerability of Persister Cancer Cells

H4K20me3-Mediated Repression of Inflammatory Genes is a Characteristic and Targetable Vulnerability of Persister Cancer Cells

Ramponi, Valentina; Richart, Laia; Kovatcheva, Marta; Stephan-Otto Attolini, Camille; Capellades, Jordi; Lord, Alice E; Yanes, Oscar; Ficz, Gabriella; Serrano, Manuel

DOI: PMID:

Abstract

Anti-cancer therapies can induce cellular senescence or drug-tolerant persistence, two types of proliferative arrest that differ in their stability. While senescence is highly stable, persistent cells efficiently resume proliferation upon therapy termination resulting in tumor relapse. Here, we used mTOR/PI3K inhibition to develop and characterize a model of persistence-associated proliferative arrest in human cancer cells of various origins. This allowed us to compare the same cancer cell lines under the two types of proliferative arrest. 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 into 1C metabolism. By investigating the relationship between 1C metabolism and the epigenetic regulation of transcription, we found that the repressive heterochromatic mark H4K20me3 was enriched at the promoters of SASP and interferon response genes in persister cells, while it was absent in 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.

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