Differentially regulated gene expression in quiescence versus senescence and identification of ARID5A as a quiescence associated marker

Anwar, Tarique; Sen, Bijoya; Aggarwal, Savera; Nath, Rhisita; Pathak, Niteen; Katoch, Ajay; Aiyaz, Mohamed; Trehanpati, Nirupma; Khosla, Sanjeev; Ramakrishna, Gayatri

doi:10.1002/jcp.26227

Cited by 10 publications

(6 citation statements)

References 51 publications

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“…This is also observed when a cell enters into quiescent state under serum-deprived conditions. In line with this, we find that the expression of quiescent characteristic genes Tob1, Tob2, Arid5a , and Btg2 (Tzachanis et al , 2001; Coller et al , 2006; Anwar et al , 2018) and transcription factors Klf2 (Buckley et al , 2001) and Foxo3 (Gopinath et al , 2014) increased in both geometries in response to compressive force. In addition, the expression of miR29a and miR221, microRNA genes reported to be down-regulated during quiescence (Medina et al , 2008; Suh et al , 2012) also reduced in response to compressive force (Figure 6H).…”

Section: Resultssupporting

confidence: 84%

Compressive force induces reversible chromatin condensation and cell geometry–dependent transcriptional response

Damodaran

Venkatachalapathy

Alisafaei

et al. 2018

MBoC

120

124

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Fibroblasts exhibit heterogeneous cell geometries in tissues and integrate both mechanical and biochemical signals in their local microenvironment to regulate genomic programs via chromatin remodelling. While in connective tissues fibroblasts experience tensile and compressive forces (CFs), the role of compressive forces in regulating cell behavior and, in particular, the impact of cell geometry in modulating transcriptional response to such extrinsic mechanical forces is unclear. Here we show that CF on geometrically well-defined mouse fibroblast cells reduces actomyosin contractility and shuttles histone deacetylase 3 (HDAC3) into the nucleus. HDAC3 then triggers an increase in the heterochromatin content by initiating removal of acetylation marks on the histone tails. This suggests that, in response to CF, fibroblasts condense their chromatin and enter into a transcriptionally less active and quiescent states as also revealed by transcriptome analysis. On removal of CF, the alteration in chromatin condensation was reversed. We also present a quantitative model linking CF-dependent changes in actomyosin contractility leading to chromatin condensation. Further, transcriptome analysis also revealed that the transcriptional response of cells to CF was geometry dependent. Collectively, our results suggest that CFs induce chromatin condensation and geometry-dependent differential transcriptional response in fibroblasts that allows maintenance of tissue homeostasis.

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Section: Resultssupporting

confidence: 84%

Compressive force induces reversible chromatin condensation and cell geometry–dependent transcriptional response

Damodaran

Venkatachalapathy

Alisafaei

et al. 2018

MBoC

120

124

View full text Add to dashboard Cite

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“…3, B and C). Two non–breast cell lines that are TP53 wild type and undergo chemotherapy-induced senescence, A549 lung adenocarcinoma and U2OS osteosarcoma (Litwiniec et al, 2010; Anwar et al, 2018), also engulfed neighboring NT cells 7–8 d after doxorubicin treatment (Fig. 3, D and E).…”

Section: Resultsmentioning

confidence: 95%

Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival

Tonnessen-Murray

Frey

Rao

et al. 2019

Journal of Cell Biology

110

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In chemotherapy-treated breast cancer, wild-type p53 preferentially induces senescence over apoptosis, resulting in a persisting cell population constituting residual disease that drives relapse and poor patient survival via the senescence-associated secretory phenotype. Understanding the properties of tumor cells that allow survival after chemotherapy treatment is paramount. Using time-lapse and confocal microscopy to observe interactions of cells in treated tumors, we show here that chemotherapy-induced senescent cells frequently engulf both neighboring senescent or nonsenescent tumor cells at a remarkable frequency. Engulfed cells are processed through the lysosome and broken down, and cells that have engulfed others obtain a survival advantage. Gene expression analysis showed a marked up-regulation of conserved macrophage-like program of engulfment in chemotherapy-induced senescent cell lines and tumors. Our data suggest compelling explanations for how senescent cells persist in dormancy, how they manage the metabolically expensive process of cytokine production that drives relapse in those tumors that respond the worst, and a function for their expanded lysosomal compartment.

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“…ABT-263 preferentially reduced cell number in senescent, TP53 wild-type breast cancer cell lines SKBR7, Cal51, 4226, and two other cell lines shown to undergo chemotherapyinduced senescence: U2OS (osteosarcoma) [52], and A549 (lung adenocarcinoma) [53]. The number of proliferating cells was unchanged by ABT-263 treatment (Fig.…”

Section: Abt-263 Induces Apoptosis Specifically In Chemotherapy-treatmentioning

confidence: 88%

BH3 mimetics selectively eliminate chemotherapy-induced senescent cells and improve response in TP53 wild-type breast cancer

et al. 2020

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TP53 wild-type breast tumors rarely undergo a complete pathological response after chemotherapy treatment. These patients have an extremely poor survival rate and studies show these tumors preferentially undergo senescence instead of apoptosis. These senescent cells persist after chemotherapy and secrete cytokines and chemokines comprising the senescence associated secretory phenotype, which promotes survival, proliferation, and metastasis. We hypothesized that eliminating senescent tumor cells would improve chemotherapy response and extend survival. Previous studies have shown "senolytic" agents selectively kill senescent normal cells, but their efficacy in killing chemotherapy-induced senescent cancer cells is unknown. We show that ABT-263, a BH3 mimetic that targets antiapoptotic proteins BCL2/BCL-XL/BCL-W, had no effect on proliferating cells, but rapidly and selectively induced apoptosis in a subset of chemotherapy-treated cancer cells, though sensitivity required days to develop. Low NOXA expression conferred resistance to ABT-263 in some cells, necessitating additional MCL1 inhibition. Gene editing confirmed breast cancer cells relied on BCL-XL or BCL-XL/MCL1 for survival in senescence. In a mouse model of breast cancer, ABT-263 treatment following chemotherapy led to apoptosis, greater tumor regression, and longer survival. Our results reveal cancer cells that have survived chemotherapy by entering senescence can be eliminated using BH3 mimetic drugs that target BCL-XL or BCL-XL/MCL1. These drugs could help minimize residual disease and extend survival in breast cancer patients that otherwise have a poor prognosis and are most in need of improved therapies.

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Differentially regulated gene expression in quiescence versus senescence and identification of ARID5A as a quiescence associated marker

Cited by 10 publications

References 51 publications

Compressive force induces reversible chromatin condensation and cell geometry–dependent transcriptional response

Compressive force induces reversible chromatin condensation and cell geometry–dependent transcriptional response

Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival

BH3 mimetics selectively eliminate chemotherapy-induced senescent cells and improve response in TP53 wild-type breast cancer

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