Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming

Romero, Octavio A.; Verdura, Sara; Torres-Diz, Manuel; Gómez, Antonio; Morán, Sebastian; Condom, Enric; Esteller, Manel; Villanueva, Alberto; Sanchez-Cespedes, Montse

doi:10.1038/onc.2016.296

Cited by 9 publications

(13 citation statements)

References 50 publications

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“…We have shown that MYC interacts with the canonical binding site of this motif and, therefore, is likely to compete with other binding partners of the SWI/SNF complex. Interestingly, a recent paper has suggested that when MYC is overexpressed it could compete with prodifferentiation transcription factors for binding to the SWI/SNF complex . Furthermore, while this study was being completed Yan et al .…”

Section: Discussionmentioning

confidence: 91%

The structure of INI1/hSNF5 RPT1 and its interactions with the c‐MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex

et al. 2018

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c-MYC and the SWI/SNF chromatin remodeling complex act as master regulators of transcription, and play a key role in human cancer. Although they are known to interact, the molecular details of their interaction are lacking. We have determined the structure of the RPT1 region of the INI1/hSNF5/BAF47/SMARCB1 subunit of the SWI/SNF complex that acts as a c-MYC-binding domain, and have localized the interaction regions on both INI1 and on the c-MYC:MAX heterodimer. c-MYC interacts with a highly conserved groove on INI1, while INI1 binds to the c-MYC helix-loop-helix region. The binding site overlaps with the c-MYC DNA-binding region, and we show that binding of INI1 and E-box DNA to c-MYC:MAX are mutually exclusive.

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Section: Discussionmentioning

confidence: 91%

The structure of INI1/hSNF5 RPT1 and its interactions with the c‐MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex

et al. 2018

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“…To this end, we rst grew two of the SMARCA4def (DMS114 and H841) and one MYCamp (DMS273) cell lines subcutaneously into the back of the mice (n = 3 mice/cell line). Once the solid tumour had entered the exponential growth phase, mice were euthanized, and the tumours we minced into small fragments and orthotopically implanted into the lungs of another cohort of mice, as previously described 20,27 , to generate the orthotopic tumours. We randomly assigned the animals, implanted with each of the tumours, to treatment or vehicle groups of mice.…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, components of the SWI/SNF complex bind to various nuclear receptors (e.g., oestrogen, androgen, glucocorticoid and retinoid receptors), thereby adapting the gene expression programs to the demands of the cell environment [16][17][18][19] . We have reported that SMARCA4 is required to promote cell growth inhibition triggered by corticoids and retinoids in cancer cells 6 , and that such effects are enhanced by combination with the pan-histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA) 20 . We observed that MYC-ampli ed but not SMARCA4-mutant cancer cells, were sensitive to these treatments.…”

Section: Introductionmentioning

confidence: 99%

SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade

Romero

Vilarrubi

Alburquerque-Béjar

et al. 2020

Preprint

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Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. This is associated with impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and with a strong dependency on these histone demethylases, so that its inhibition compromises cell viability in the SMARCA4-mutant cells. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. Our results highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients.

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“…Since it is established that epigenetic modulation can enhance responses to retinoid-based treatments 53 – 55 , we provide further evidence that DNA methylation can impact the atRA-inducibility of select genes. On the other hand, the use of the histone deacetylase inhibitor, trichostatin A (TSA), revealed limited contributions of histone acetylation to the regulation of atRA-inducible genes.…”

Section: Introductionmentioning

confidence: 80%

Profiling of the transcriptional response to all-trans retinoic acid in breast cancer cells reveals RARE-independent mechanisms of gene expression

Coyle

Maxwell

Thomas

et al. 2017

Sci Rep

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Retinoids, derivatives of vitamin A, are key physiological molecules with regulatory effects on cell differentiation, proliferation and apoptosis. As a result, they are of interest for cancer therapy. Specifically, models of breast cancer have varied responses to manipulations of retinoid signaling. This study characterizes the transcriptional response of MDA-MB-231 and MDA-MB-468 breast cancer cells to retinaldehyde dehydrogenase 1A3 (ALDH1A3) and all-trans retinoic acid (atRA). We demonstrate limited overlap between ALDH1A3-induced gene expression and atRA-induced gene expression in both cell lines, suggesting that the function of ALDH1A3 in breast cancer progression extends beyond its role as a retinaldehyde dehydrogenase. Our data reveals divergent transcriptional responses to atRA, which are largely independent of genomic retinoic acid response elements (RAREs) and consistent with the opposing responses of MDA-MB-231 and MDA-MB-468 to in vivo atRA treatment. We identify transcription factors associated with each gene set. Manipulation of the IRF1 transcription factor demonstrates that it is the level of atRA-inducible and epigenetically regulated transcription factors that determine expression of target genes (e.g. CTSS, cathepsin S). This study provides a paradigm for complex responses of breast cancer models to atRA treatment, and illustrates the need to characterize RARE-independent responses to atRA in a variety of models.

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Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming

Cited by 9 publications

References 50 publications

The structure of INI1/hSNF5 RPT1 and its interactions with the c‐MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex

The structure of INI1/hSNF5 RPT1 and its interactions with the c‐MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex

SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade

Profiling of the transcriptional response to all-trans retinoic acid in breast cancer cells reveals RARE-independent mechanisms of gene expression

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