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Chromatin Remodeling Underlies the Senescence-Associated Secretory Phenotype of Tumor Stromal Fibroblasts That Supports Cancer Progression
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Abstract
Age is a major risk factor for the development of cancer. Senescent fibroblasts, which accumulate with age, secrete protumorigenic factors collectively referred to as the senescence-associated secretory phenotype (SASP). Here, we examined the molecular mechanisms that control SASP activation, focusing on the known SASP factor osteopontin (OPN). We found that expression of the canonical SASP members interleukin (IL)-6 and IL-8, but not OPN, were dependent upon a persistent DNA damage response (DDR) as evidenced by ATM and NF-κB activation. Treatment with several histone deacetylase (HDAC) inhibitors robustly activated SASP in the absence of DNA breaks, suggesting that DDR-dependent SASP activation occurs in response to chromatin remodeling rather than physical breaks in DNA. In the setting of HDAC inhibition, IL-6 and IL-8 expression remained dependent upon ATM and NF-κB, while OPN expression remained independent of these factors. Further analysis revealed that HDAC1 inhibition was sufficient to induce OPN expression, which is interesting given that loss of HDAC1 expression correlates with increased OPN expression within the stromal compartment of invasive breast cancers. Importantly, fibroblasts treated with HDAC inhibitors promoted tumor growth in vivo. Our findings therefore indicate that HDAC modulation plays an important role in stromal cell activation, with important implications for the use of HDAC inhibitors in the treatment of cancer. Cancer Res; 72(9); 2251–61. ©2012 AACR.
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“The SASP is primarily a property of cells that senesce owing to, or accompanied by, genomic damage or epigenomic perturbation.”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [67]
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“In contrast, cells that senesce owing to DNA damage, dysfunctional telomeres, epigenomic disruption, mitogenic signals, oxidative stress, and other senescence-inducing stimuli develop a SASP of varying qualities and robustness (32, 33, 42, 67, 94, 96, 99, 100, 112–114).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [67]
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“The SASP is also positively regulated by the transcription factors nuclear factor κB (NF-κB) (57, 67, 99) and C/EBP-β (100) (Figure 2).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [67]
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“Both AP-1 and NFKB1 are implicated in establishing senescence and regulating the SASP.43,44”
From Cellular senescence in human liver under normal aging and cancer (2026) · cites this paper as [44]
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“Many, but not all, SASP components are positively regulated by the DDR proteins ATM, NBS1 (Nijmegen breakage syndrome 1), and CHK2 (checkpoint kinase 2) (42, 67).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [67]
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“at millimolar doses, TSA has been shown to promote senescence and development of the SASP (Pazolli et al. 2012)”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Pazolli et al. 2012
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Metadata
- Authors
- Pazolli, E., Alspach, E., Milczarek, A., Prior, J., Piwnica-Worms, D., & Stewart, S. A.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Stewart, Sheila A.
- ORCID
- Venue
- Cancer Research
- Published
- 2012-04-30
- Volume
- 72
- Issue
- 9
- Pages
- 2251-2261
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3605047
- OpenAlex
- W1975799119
- Cited by
- 192
- References
- 54
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 14 · 2023: 19 · 2022: 12 · 2021: 25 · 2020: 14 · 2019: 10 · 2018: 14 · 2017: 8 · 2016: 12 · 2015: 13 · 2014: 11 · 2013: 13 · 2012: 6
- FWCI
- 9.22
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (P50 CA94056, P50CA094056, R01CA130919, T32CA113275)
- National Institute of General Medical Sciences (T32GM007067)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- senescence-associated secretory phenotype, tumor stromal fibroblasts, chromatin remodeling, histone deacetylase inhibitors, HDAC1, osteopontin, interleukin-6, interleukin-8, DNA damage response, ATM, NF-κB, aging and cancer, tumor progression, breast cancer stroma, tumor growth
- MeSH terms
- Animals, Breast Neoplasms, Chromatin, DNA Damage, Female, Fibroblasts, Humans, Phenotype, RNA, Messenger, Interleukin-6, Interleukin-8, Mice, SCID, Mice, Inbred NOD, Cellular Senescence, Stromal Cells, Disease Progression, Mice, Osteopontin, Histone Deacetylase 1, Histone Deacetylase Inhibitors
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