SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer

Tordella, Luca; Khan, Sadaf; Hohmeyer, Anja; Banito, Ana; Klotz, Sabrina; Raguz, Selina; Martin, Nadine; Dhamarlingam, Gopuraja; Carroll, Thomas; Meljem, José Mario González; Deswal, Sumit; Martı́nez-Barberá, Juan Pedro; García‐Escudero, Ramón; Zuber, Johannes; Zender, Lars; Gil, Jesús

doi:10.1101/gad.286112.116

Cited by 49 publications

(36 citation statements)

References 44 publications

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“…We confirmed ability of wild type ARID1B to cause reduction in cell viability and growth 9, 30 in PaCa cells using crystal violet staining and MTT assay (figures 3d-e). Surprisingly however, the cytoplasmic form of ARID1B appeared to exhibit a neo-morphic function causing a significant increase in cell viability in the same assays (figures 3d-e).…”

Section: Resultssupporting

confidence: 65%

Cytoplasm localized ARID1B promotes oncogenesis in pancreatic cancer by activating RAF-ERK signaling

Animireddy

Kavadipula

Kotapalli

et al. 2019

Preprint

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The ARID1B/BAF250b subunit of the human SWI/SNF chromatin remodeling complex is a canonical nuclear tumor suppressor. Immunohistochemistry on a pancreatic cancer tissue microarray revealed significant ARID1B cytoplasmic localization that correlated with advanced tumor stage and lymph node positivity. Identification of the nuclear localization signal (NLS) using in silico prediction and subcellular localization studies facilitated evaluation of a possible cytoplasmic function for ARID1B. A cytoplasm-restricted ARID1B-NLS mutant was significantly compromised to regulate transcription activation and tumor suppression functions, as expected. Surprisingly however, cytoplasm-localized ARID1B could bind c-RAF and PPP1CA causing stimulation of RAS-RAF-ERK signaling and β-catenin transcription activity in pancreatic cancer cells. More importantly, cytoplasmic ARID1B resulted in an induction of cell growth and migration in pancreatic cancer cell lines that was dependent on ERK signaling and caused increased tumorigenesis in nude mice. NLS peptides representing mutations identified from pancreatic cancer samples exhibiting ARID1B cytoplasmic localization or curated from cancer somatic mutation database were significantly compromised to effect nuclear localization of a reporter protein. ARID1B cytoplasmic localization correlated significantly with active forms of ERK and β-catenin in primary pancreatic tumor samples. ARID1B may therefore promote oncogenesis through non-canonical cytoplasm-based gain of function mechanisms in addition to dysregulation in the nucleus.

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Section: Resultssupporting

confidence: 65%

Cytoplasm localized ARID1B promotes oncogenesis in pancreatic cancer by activating RAF-ERK signaling

Animireddy

Kavadipula

Kotapalli

et al. 2019

Preprint

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“…The precise molecular mechanisms by which alterations in chromatin remodeling complexes promote cancer development are not sufficiently understood. Interactions with well-described cancer genes like TP53, RB or MYC have been described [35][36][37] . In addition to this, they play essential roles in the activation of differentiation and the suppression of proliferative programs of many cellular lineages 38 .…”

Section: Discussionmentioning

confidence: 99%

ARID2deficiency promotes tumor progression and is associated with higher sensitivity to PARP inhibition in lung cancer

Moreno

González-Silva

Monterde

et al. 2020

Preprint

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Red de Enfermedades Raras byimpairing DNA repair. Importantly, our results indicate that ARID2-deficiency could be(CIBERER).Tenerife, Spain. RUNNING TITLEARID2-deficiency directs sensitivity to PARP inhibition. KEY WORDSARID2/Lung Cancer/Next-generation sequencing technologies/SWI-SNF FINANCIAL SUPPORTI. ABSTRACTThe survival rate in lung cancer remains stubbornly low and there is an urgent need for the identification of new therapeutic targets. Last decade's research has evidenced a clear role of chromatin structure in cancer development and several members of the SWI/SNF chromatin remodeling complexes have been described altered in different tumor types. Nevertheless, the precise mechanisms of their impact on cancer progression, as well as the application of this knowledge to cancer patient management are largely unknown.In this study, we have performed targeted sequencing of a cohort of lung cancer patients on genes involved in chromatin structure, as well as functional experiments to identify the molecular mechanisms linking alterations of chromatin remodeling genes and tumor development.We have identified ARID2 production loss in 20% of lung cancer patients. Additionally, we have shown that ARID2-deficiency provokes profound chromatin structural changes, alters the transcriptional programme and impairs DNA repair which bolster the proliferative and metastatic potential of the cells both in vitro and in vivo. Moreover, we have demonstrated that ARID2 deficiency significantly affects the sensitivity of the cells to PARP inhibition.All these results support that ARID2 is a bona-fide tumor suppressor gene in lung cancer that might be exploited therapeutically.

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“…After the staining, the slides were counterstained with eosin, dehydrated, mounted and analysed by phase‐contrast microscopy. SA‐β‐Gal tissue staining was quantified using ImageJ software (NIH) by measuring the percentage of stained area in each section and multiplying it by its mean intensity value as described before (Tordella et al, 2016). To exclude the luminal spaces in the lung sections, the percentage of SA‐β‐Gal‐positive area was divided by the total lung area, as determined by eosin‐positive area using ImageJ (NIH).…”

Section: Methodsmentioning

confidence: 99%

Galactose‐modified duocarmycin prodrugs as senolytics

et al. 2020

Self Cite

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Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with cancer, fibrosis and many age‐related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence‐associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal β‐galactosidase, and this has been exploited as a marker for senescence (senescence‐associated β‐galactosidase activity). Consequently, we hypothesized that galactose‐modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose‐modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal β‐galactosidase (GLB1)‐dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole‐body irradiation treatment of mice. Moreover, taking advantage of a mouse model of adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD prodrug selectively reduced the number of β‐catenin‐positive preneoplastic senescent cells. In summary, the above results make a case for testing the potential of galactose‐modified duocarmycin prodrugs to treat senescence‐related pathologies.

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SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer

Cited by 49 publications

References 44 publications

Cytoplasm localized ARID1B promotes oncogenesis in pancreatic cancer by activating RAF-ERK signaling

Cytoplasm localized ARID1B promotes oncogenesis in pancreatic cancer by activating RAF-ERK signaling

ARID2deficiency promotes tumor progression and is associated with higher sensitivity to PARP inhibition in lung cancer

Galactose‐modified duocarmycin prodrugs as senolytics

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