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CDK4/6 inhibition induces a senescence-associated secretory phenotype via delayed NF-κB activation [CUT&Run]

ABSTRACT: Cellular senescence consists of regulated phenotypes associated with permanent exit from the cell cycle in response to stressors such as genomic instability. The consequences of senescence go beyond individual cells due to the senescence associated secretory phenotype (SASP), which can induce inflammation in neighboring cells. Some cancers respond to CDK4/6 inhibitors (CDK4/6i) with a senescence-like phenotype in the absence of extensive DNA damage. We asked how the SASP and the transcriptional regulatory profile triggered by CDK4/6i-driven arrest compares to the canonical NF-κB-regulated SASP triggered by DNA damage. We profiled the dynamics of transcriptional regulation in response to the CDK4/6i, palbociclib, and the DNA damaging agent, doxorubicin. We found upregulation of NF-κB driven-SASP genes was shared across both drugs, although delayed in CDK4/6i, coinciding with slower enhancer activation and epigenetic changes. ATM/ATR inhibition did not affect CDK4/6i-induced NF-κB nuclear localization, suggesting an alternative upstream activator. Inhibiting NF-κB suppressed the expression of SASP genes without reversing stable arrest, pointing to SASP manipulation as a potential therapeutic strategy and providing insights into controversies regarding cell cycle arrest-driven SASP.

ORGANISM(S): Homo sapiens

PROVIDER: GSE336040 | GEO | 2026/06/22

REPOSITORIES: GEO

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CDK4/6 inhibition induces a senescence-associated secretory phenotype via delayed NF-κB activation [CUT&Tag]

Project description:Cellular senescence consists of regulated phenotypes associated with permanent exit from the cell cycle in response to stressors such as genomic instability. The consequences of senescence go beyond individual cells due to the senescence associated secretory phenotype (SASP), which can induce inflammation in neighboring cells. Some cancers respond to CDK4/6 inhibitors (CDK4/6i) with a senescence-like phenotype in the absence of extensive DNA damage. We asked how the SASP and the transcriptional regulatory profile triggered by CDK4/6i-driven arrest compares to the canonical NF-κB-regulated SASP triggered by DNA damage. We profiled the dynamics of transcriptional regulation in response to the CDK4/6i, palbociclib, and the DNA damaging agent, doxorubicin. We found upregulation of NF-κB driven-SASP genes was shared across both drugs, although delayed in CDK4/6i, coinciding with slower enhancer activation and epigenetic changes. ATM/ATR inhibition did not affect CDK4/6i-induced NF-κB nuclear localization, suggesting an alternative upstream activator. Inhibiting NF-κB suppressed the expression of SASP genes without reversing stable arrest, pointing to SASP manipulation as a potential therapeutic strategy and providing insights into controversies regarding cell cycle arrest-driven SASP.

2026-06-22 | GSE295261 | GEO

CDK4/6 inhibition induces a senescence-associated secretory phenotype via delayed NF-κB activation

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Cyclin-dependent kinase 6 is a chromatin-bound cofactor for nuclear factor kappaB-dependent gene expression [Agilent]

Project description:Given the intimate link between inflammation and dysregulated cell proliferation in cancer we investigated cytokine-triggered gene expression in different cell cycle stages. High density microarray analysis revealed that G1 release primes and cooperates with the cytokine-driven gene response. This effect is transmitted through CDK6 which shares the ability to regulate expression of inflammatory genes with its functional homologue CDK4. CDK6 contributes to the regulation of inflammatory gene expression by physical and functional cooperation with the NF-κB subunit p65 in the nucleus. ChIPSeq experiments showed a tight co-recruitment of CDK6 and p65 to enhancers and promoters of many transcriptionally active NF-κB target genes. While CDK6 recruitment to distinct chromatin regions of inflammatory target genes had no effect on histone modifications, it was essential for proper loading of NF-κB p65 to its cognate binding sites and for the function of p65 coactivators such as TRIP6. Furthermore, cytokine-inducible nuclear translocation and chromatin association of CDK6 depends on the kinase activity of TAK1 and p38. These results have widespread biological implications, as aberrant CDK6 expression or activation that is frequently observed in human tumors cooperates with NF-κB to shape the cytokine- and chemokine-repertoire in chronic inflammation and cancer. Four sets of experiments were performed in total (Exp1-4). Within each of these sets biological duplicates (Rep1-2) were included and analyzed. HeLa control cells or cells with established shRNA-mediated knockdown of CDK4 or CDK6 were analyzed. Cells were subjected to cell cycle arrest or were released from the arrested state for 6h. Cells were treated for 30 minutes with Interleukin-1-alpha at the arrested state or after release or were left untreated.

2013-12-31 | E-GEOD-52465 | biostudies-arrayexpress

ATAC-seq of IMR90 cells during OIS under TPR depletion

Project description:During oncogene-induced senescence there are striking changes in the structure of the nucleus and the organisation of heterochromatin. This is accompanied by activation of a pro-inflammatory gene expression programme – the senescence associated secretory phenotype (SASP) – driven by transcription factors such as NF-κB. Here we show that TPR, a protein of the nuclear pore complex basket, is required for the very early activation of NF- κB signalling during the stress-response phase of oncogene-induced senescence. This is prior to activation of the SASP and occurs without affecting NF-κB nuclear import. We show that TPR is required for the activation of TBK1 signalling at these early stages of senescence and we link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments thought to bleb off from the nuclear periphery. These cytoplasmic chromatin fragments appear to lack nuclear pore components. Our data suggest that TPR at the nuclear pore is involved in the loss of structural integrity of the nuclear periphery during senescence. We propose that this acts as a trigger for activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP, during senescence.

2024-12-19 | GSE264390 | GEO

RNA-seq of IMR90 cells during OIS under TPR depletion

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CDK4/6 inhibitor-mediated cell overgrowth triggers an osmotic stress response and chronic p38MAPK activation to promote long-term cell cycle arrest

Project description:<p>Cell size and the cell cycle are intrinsically coupled and abnormal increases in cell size are associated with senescence and permanent cell cycle arrest. The mechanism by which overgrowth primes cells to withdraw from the cell cycle remains unknown. We investigate this here using CDK4/6 inhibitors that arrest cell cycle progression during G0/G1 and are used in the clinic to treat ER+/HER2- metastatic breast cancer. We demonstrate that CDK4/6 inhibition promotes cellular overgrowth during G0/G1, causing p38MAPK-p53-p21-dependent cell cycle withdrawal. We find that cell cycle withdrawal is triggered by two waves of p21 induction. First, overgrowth during a long-term G0/G1 arrest induces an osmotic stress response. This stress response produces the first wave of p21 induction. Second, when CDK4/6 inhibitors are removed, a fraction of cells escape long term G0/G1 arrest and enter S-phase where overgrowth-driven replication stress results in a second wave of p21 induction that causes cell cycle withdrawal from G2, or the subsequent G1. We propose a model whereby both waves of p21 induction contribute to promote permanent cell cycle arrest. This model could explain why cellular hypertrophy is associated with senescence and why CDK4/6 inhibitors have long-lasting effects in patients.</p>

2025-10-24 | MTBLS5868 | MetaboLights

Atypical NF-κB activation by endogenous DNA damage drives senescence and aging

Project description:Chronic activation of NF-κB contributes to senescence and aging, but how endogenous DNA damage engages this pathway in vivo remains unclear. NF-κB can be activated by an atypical pathway in which genotoxic stress triggers ATM-dependent sumoylation of the regulatory subunit NEMO, yet the role of this axis in senescence and aging has not been tested. Here we introduced a knock-in NEMO double-lysine mutant (NEMO-DK) that prevents sumoylation at the conserved sites required for DNA damage-induced NF-κB activation, and examined its impact in Ercc1-/∆ mice, a model of accelerated, DNA damage-driven aging. We demonstrated that NEMO-DK markedly reduced senescence and SASP in primary fibroblasts and across multiple tissues, improved liver and skeletal muscle pathology, attenuated intervertebral disc degeneration, significantly delayed the onset and progression of aging symptoms and extended healthspan. These findings identify DNA damage-induced NEMO sumoylation as a key driver of NF-κB-mediated senescence in vivo and suggest that the atypical NF-κB pathway is a potential therapeutic target to mitigate aging-associated diseases.

2026-01-01 | GSE314144 | GEO

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2024-11-18 | E-MTAB-14085 | biostudies-arrayexpress

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Project description:Cellular senescence, a state of irreversible cell cycle arrest, contributes to aging and age-related diseases through the accumulation of senescent cells and their secretion of a pro-inflammatory senescence-associated secretory phenotype (SASP).Recent studies indicated that extracellular vesicles (EVs) as key SASP components mediating intercellular communication. Here, we investigated the effects of human trophoblast stem cell secretome and EVs (hTSC-S, hTSC-EVs) on cellular senescence. Our results show that hTSC-S and hTSC-EVs reduce SASP-associated mRNAs and cytokines, including CXCL1 and GDF15, and suppress NF-κB activation in senescent WI-38 cells. Proteomic analysis revealed an enrichment of ECM-remodeling proteins in hTSC-EVs, suggesting restorative properties. In vivo, hTSC-S decreased GDF15, CXCL1, and markers of DNA damage in aged mice, underscoring its therapeutic potential to modulate SASP and promote healthier aging.

2026-01-21 | GSE282054 | GEO

CDK4/6 inhibitor-mediated cell overgrowth triggers an osmotic stress response

Project description:Cell size and the cell cycle are intrinsically coupled and abnormal increases in cell size are associated with senescence and permanent cell cycle arrest. The mechanism by which overgrowth primes cells to withdraw from the cell cycle remains unknown. We investigate this here using CDK4/6 inhibitors that arrest cell cycle progression during G0/G1 and are used in the clinic to treat ER+/HER2- metastatic breast cancer. We demonstrate that CDK4/6 inhibition promotes cellular overgrowth during G0/G1, causing p38MAPK-p53-p21-dependent cell cycle withdrawal. We find that cell cycle withdrawal is triggered by two waves of p21 induction. First, overgrowth during a long-term G0/G1 arrest induces an osmotic stress response. This stress response produces the first wave of p21 induction. Second, when CDK4/6 inhibitors are removed, a fraction of cells escape long term G0/G1 arrest and enter S-phase where overgrowth-driven replication stress results in a second wave of p21 induction that causes cell cycle withdrawal from G2, or the subsequent G1. We propose a model whereby both waves of p21 induction contribute to promote permanent cell cycle arrest. This model could explain why cellular hypertrophy is associated with senescence and why CDK4/6 inhibitors have long-lasting effects in patients.

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