A cmap-enabled gene expression signature-matching approach identifies small-molecule inducers of accelerated cell senescence

Wu, Duojie; Pepowski, Brett; Takahashi, Satoe; Kron, Stephen J.

doi:10.1186/s12864-019-5653-x

Cited by 12 publications

(6 citation statements)

References 57 publications

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“…Among them, FOXA1, PLAT, CD44, FGF5, DIO2 and other genes are upregulated, whereas PLCB1, SETBP1, EHD3, ZNF423, PHGDH and other genes are downregulated in multiple senescence systems(Chan et al, 2019; Cho et al, 2019; Galanos et al, 2016; Hari et al, 2019; Hernandez-Segura et al, 2017; Komseli et al, 2018; Lau, Porciuncula, Yu, Iwakura, & David, 2019; Leveque et al, 2019; Q. Li et al, 2013; Limbad et al, 2020; Lowe & Raj, 2014; Nagano et al, 2016; Pan et al, 2019; Pantazi et al, 2019; Suwan et al, 2009; Wu, Pepowski, Takahashi, & Kron, 2019; Zhou et al, 2010), as are consistent with our results. These genes are located in or near the regions of IARs or DARs respectively.…”

Section: Resultssupporting

confidence: 92%

ATF3 drives senescence by reconstructing accessible chromatin profiles

Zhang

Guan

et al. 2020

Preprint

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Chromatin architecture and gene expression profile undergo tremendous reestablishment during senescence. However, the regulatory mechanism between chromatin reconstruction and gene expression in senescence remain elusive. The chromatin accessibility is an excellent perspective to reveal the latent regulatory elements. Thus, we depicted the landscapes of chromatin accessibility and gene expression during HUVECs senescence. We found that chromatin accessibilities are re-distributed during senescence. The senescence related increased accessible regions (IARs) and the decreased accessible regions (DARs) are mainly distributed in distal intergenic regions. The DARs are correlated with the function declines caused by senescence, whereas the IARs are involved in the regulation for senescence program. Moreover, the heterochromatin contributes most of IARs in senescent cells. We identified that the AP-1 transcription factors, especially ATF3 is responsible for driving chromatin accessibility reconstruction in IARs. In particular, DNA methylation is negatively correlated with chromatin accessibility during senescence. AP-1 motifs with low DNA methylation may improve their binding affinity in IARs and further opens the chromatin nearby. Our results described a dynamic landscape of chromatin accessibility whose remodeling contributes to the senescence program. And we identified a cellular senescence regulator, AP-1, which promotes senescence through organizing the accessibility profile in IARs.

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Section: Resultssupporting

confidence: 92%

ATF3 drives senescence by reconstructing accessible chromatin profiles

Zhang

Guan

et al. 2020

Preprint

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“…However, there is relatively limited literature on the capacity of SERMs to induce senescence. Fulvestrant and tamoxifen have both been shown to induce senescent phenotypes in breast cancer cell lines, but the percentage of senescence induced in the population is typically less than 50% [92,94,95]. One study using the charcoal-stripped-serum (CSS) model, which removes all steroid hormones from the medium, demonstrated a more robust senescent phenotype in MCF-7 cells in response to estrogen deprivation [93].…”

Section: Hormonal Therapymentioning

confidence: 99%

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Saleh

Bloukh

Carpenter

et al. 2020

Cancers

206

150

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For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse.

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“…while being rejected by CMap 1 (Zador et al, 2018). On the other hand, there are also anecdotal reports of positive results, in which researchers have experimentally verified the biological effects of candidate drugs recommended by CMap 1 (Braconi et al, 2009;Brum et al, 2015Brum et al, , 2018Byun et al, 2019;Johnstone et al, 2012;Luo et al, 2019;Schanstra et al, 2019;Wang et al, 2019;Wu et al, 2019) or CMap 2 (Ferguson et al, 2018;Leung et al, 2019;Manzotti et al, 2019;Ryals et al, 2018). An attempt to address the reproducibility question was presented by De Abrew et al, in which they generated an independent CMap-style dataset for 34 compounds in four cell lines (De Abrew et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Connectivity Map shows limited reproducibility in drug repositioning

Lim

Pavlidis

2019

Preprint

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The Connectivity Map (CMap) is a popular resource designed for data-driven drug repositioning using a large transcriptomic compendium. However, evaluations of its performance are limited. We used two iterations of CMap (CMap 1 and 2) to assess their comparability and reliability. We queried CMap 2 with CMap 1-derived signatures, expecting CMap 2 would highly prioritize the queried compounds; success rate was 17%. Analysis of previously published prioritizations yielded similar results. Low recall is caused by low differential expression (DE) reproducibility both between CMaps and within each CMap.DE strength was predictive of reproducibility, and is influenced by compound concentration and cell-line responsiveness. Reproducibility of CMap 2 sample expression levels was also lower than expected. We attempted to identify the "better" CMap by comparison with a third dataset, but they were mutually discordant. Our findings have implications for CMap usage and we suggest steps for investigators to limit false positives.

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A cmap-enabled gene expression signature-matching approach identifies small-molecule inducers of accelerated cell senescence

Cited by 12 publications

References 57 publications

ATF3 drives senescence by reconstructing accessible chromatin profiles

ATF3 drives senescence by reconstructing accessible chromatin profiles

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Evaluation of Connectivity Map shows limited reproducibility in drug repositioning

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