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Regulation of ribosomal gene expression and senescence by a PML-mTOR-RONIN nuclear complex in triple-negative breast cancer

Oncogene volume 44, pages 4712–4726 (2025)Cite this article

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Abstract

Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer that is associated with poor prognosis and a high risk of relapse, with limited treatment options. While the induction of senescence, a state of arrested cell growth, is generally achieved by available anticancer treatments, senescence can adversely promote tumorigenesis through an upheld augmented inflammatory state called senescence-associated secretory phenotype (SASP). Thus, the precise delineation of underlying regulatory mechanisms governing senescence is urgently needed. Herein, we investigated the beneficial anticancer senescence response elicited by silencing the expression of the promyelocytic leukemia protein (PML) in TNBC, where it exerts an oncogenic role. Functional genomics studies implicated the downregulation of a specific set of ribosomal protein (RP) genes tied to poor clinical outcome. Re-introduction of RPL38 or RPL39L alone, but not RPS14, a favorable outcome-associated RP, was sufficient to block the senescence phenotype induced by PML knockdown. RP gene regulation by PML was found to involve the assembly of a previously unrecognized PML-mTOR-RONIN transcriptional complex at their promoters. Furthermore, we show that RONIN levels are elevated in TNBC and that RONIN silencing can recapitulate the senescent phenotype of PML-deficient cells. This work offers new therapeutic insights for TNBC that involve senescence-inducing therapies or senolytics.

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Fig. 1: PML KD alters ribosome biology.
Fig. 2: PML is a transcriptional regulator of ribosomal proteins.
Fig. 3: PML interacts with mTOR at RP promoters.
Fig. 4: RONIN/THAP11 is enriched in TNBC and associates with the PML-mTOR complex.
Fig. 5: RONIN knockdown triggers senescence in TNBC cells.
Fig. 6: RPL38 or RPL39L overexpression mitigates the senescent phenotype induced by PML or RONIN silencing.

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Data availability

PML and mTOR ChIP-seq data performed in MDA-MB-231 cells, as well as RNA-seq data of shRNA-mediated knockdown of PML in MDA-MB-231 cells, have been deposited in NCBI’s Gene Expression Omnibus (GEO) and are accessible through GEO SuperSeries accession number GSE283109 encompassing SubSeries GSE283106 (shPML RNA-seq), GSE283107 (PML ChIP-seq), and GSE283108 (mTOR ChIP-seq). Gene expression data from the breast cancer METABRIC [63, 64] and TCGA PanCancer atlas cohorts were downloaded from cbioportal (https://www.cbioportal.org) [56, 57] or analyzed with bc-GenExMiner v5.1 (https://bcgenex.ico.unicancer.fr/BC-GEM/). Proteomics data from a breast cancer patient cohort were obtained from CPTAC [59]. Proteomics data of breast cancer cell lines were obtained from (1) CCLE [60] via the Dependency Map (DepMap) portal (https://depmap.org/portal/); (2) Lapek et al. [61]; or (3) Sun et al. [62]. This paper does not report original code. Source data underlying the graphs are presented in Supplementary Table 8. Uncropped immunoblots are shown in Supplementary Fig. S6. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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Acknowledgements

The authors thank members of the Giguère laboratory for assistance and critical discussions, the McGill Platform for Cellular Perturbation (MPCP), and Mr. Alain Pacis from the Canadian Centre for Computational Genomics (C3G) for help with ChIP-seq analysis. Results from examination of breast cancer mRNA-sequencing data from the TCGA-pan cancer dataset are based upon data generated by the TCGA Research Network (https://www.cancer.gov/tcga). This work was supported by a Foundation grant from the Canadian Institutes of Health Research (CIHR) to VG (FDT-156254), a Terry Fox Research Institute Team Grant (PPG-1091), and an operating grant from the Cancer Research Society (CRS-1052927). YM is supported by a Charlotte & Leo Karassik Fellowship and a FRQS Postdoctoral Fellowship. LH is supported by Canderel and Fond de recherches du Québec – Santé (FRQS) studentships. AA is supported by a CIHR studentship. PH is supported by a J.P. Collip fellowship in medical research from McGill’s Faculty of Medicine and Health Sciences (FMHS). MV was a recipient of a post-doctoral fellowship from CIHR. AR was supported by a Canderel post-doctoral fellowship.

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  1. Mathieu Vernier

    Present address: ClinSearch, Malakoff, France

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  1. Rosalind and Morris Goodman Cancer Institute, McGill University, Montréal, QC, Canada

    Younes Medkour, Catherine Rosa Dufour, Lingwei Han, Phillipe Hutton, Mirna Farhat, Anthony Alfonso, Amandine Rambur, Mathieu Vernier & Vincent Giguère

  2. Department of Biochemistry, Faculty of Medicine and Health Sciences, McGill University, Montréal, QC, Canada

    Lingwei Han, Phillipe Hutton, Mirna Farhat, Anthony Alfonso & Vincent Giguère

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Conceptualization: M Vernier, V Giguère, and CR Dufour; methodology: M Vernier, Y Medkour; investigation: Y Medkour, CR Dufour, L Han, P Hutton, M Farhat, A Alfonso, A Rambur, M Vernier, and V Giguère; writing—original draft: M Vernier, CR Dufour; Y Medkour; writing—review and editing: V Giguère; study supervision: V Giguère and M Vernier; funding acquisition: V Giguère.

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Correspondence to Mathieu Vernier or Vincent Giguère.

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Medkour, Y., Dufour, C.R., Han, L. et al. Regulation of ribosomal gene expression and senescence by a PML-mTOR-RONIN nuclear complex in triple-negative breast cancer. Oncogene 44, 4712–4726 (2025). https://doi.org/10.1038/s41388-025-03623-6

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