UNC45A Confers Resistance to Histone Deacetylase Inhibitors and Retinoic Acid

Epping, Mirjam T.; Meijer, L.; Bos, Johannes L.; Bernards, René

doi:10.1158/1541-7786.mcr-09-0187

Cited by 23 publications

(33 citation statements)

References 27 publications

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“…Our genetic results, which demonstrate the dual roles of UNC45b in affecting sarcomeric myosin and the GATA4 transcription factor during mouse cardiogenesis, are reminiscent of studies reporting the interactions of UNC-45A (A is for humans; a for other vertebrates) with the progesterone and glucocorticoid receptors (Chadli et al, 2006), and the retinoic acid receptor pathway (Epping et al, 2009). Both the hormone receptors and the retinoic acid receptor, like GATA4, perform significant roles in development and homeostasis.…”

Section: Discussionsupporting

confidence: 65%

“…9A). As suggested by previous studies with the ubiquitously expressed homolog UNC-45A, its binding to the progesterone and glucocorticoid receptors (Chadli et al, 2006) and its effects on the retinoic acid receptor alpha isoform (Epping et al, 2009), we first demonstrated that UNC-45b participated in a complex with GATA4. Plasmids of UNC-45b-FLAG and GATA4-Myc were co-transfected into HeLa S3 cells.…”

Section: Interactions Between Unc-45b and Its Client Proteinssupporting

confidence: 51%

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Dual function of the UNC-45b Chaperone with myosin and GATA4 in cardiac development

Chen

Singh

et al. 2012

Journal of Cell Science

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SummaryCardiac development requires interplay between the regulation of gene expression and the assembly of functional sarcomeric proteins. We report that UNC-45b recessive loss-of-function mutations in C3H and C57BL/6 inbred mouse strains cause arrest of cardiac morphogenesis at the formation of right heart structures and failure of contractile function. Wild-type C3H and C57BL/6 embryos at the same stage, E9.5, form actively contracting right and left atria and ventricles. The known interactions of UNC-45b as a molecular chaperone are consistent with diminished accumulation of the sarcomeric myosins, but not their mRNAs, and the resulting decreased contraction of homozygous mutant embryonic hearts. The novel finding that GATA4 accumulation is similarly decreased at the protein but not mRNA levels is also consistent with the function of UNC-45b as a chaperone. The mRNAs of known downstream targets of GATA4 during secondary cardiac field development, the cardiogenic factors Hand1, Hand2 and Nkx-2.5, are also decreased, consistent with the reduced GATA4 protein accumulation. Direct binding studies show that the UNC-45b chaperone forms physical complexes with both the alpha and beta cardiac myosins and the cardiogenic transcription factor GATA4. Co-expression of UNC-45b with GATA4 led to enhanced transcription from GATA promoters in naïve cells. These novel results suggest that the heart-specific UNC-45b isoform functions as a molecular chaperone mediating contractile function of the sarcomere and gene expression in cardiac development.

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Section: Discussionsupporting

confidence: 65%

Section: Interactions Between Unc-45b and Its Client Proteinssupporting

confidence: 51%

Dual function of the UNC-45b Chaperone with myosin and GATA4 in cardiac development

Chen

Singh

et al. 2012

Journal of Cell Science

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“…21 Additional putative targets for UNC-45A that may also be significant in breast and ovarian cancer progression are the progesterone and retinoic acid receptors. 39,42 UNC-45A proteins appear to be both regulated and putative regulatory molecules. Here, the UNC-45A 944-residue isoform is under an additional level of regulation, the presence of an additional proline-rich 15-amino-acid sequence, associated with its increased turnover through the ubiquitin-proteasome system.…”

Section: Discussionmentioning

confidence: 99%

Differential Turnover of Myosin Chaperone UNC-45A Isoforms Increases in Metastatic Human Breast Cancer

Guo

Chen

Fan³

et al. 2011

Journal of Molecular Biology

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“…The histone deacetylase inhibitor side-effect profile is low when compared with cytotoxic chemotherapy [20] . Moreover, two unbiased preclinical screens identified retinoid signal activation as the most effective method of augmenting the histone deacetylase inhibitor anti-cancer signal [21,22] . Retinoic acid receptor α (RARα), and, preferentially expressed antigen of melanoma, both repressor proteins for the retinoid signal, was shown to mediate resistance to histone deacetylase inhibitors [21] .…”

Section: Combination Therapy Improves the Anticancer Activity Of Histmentioning

confidence: 99%

“…Retinoic acid receptor α (RARα), and, preferentially expressed antigen of melanoma, both repressor proteins for the retinoid signal, was shown to mediate resistance to histone deacetylase inhibitors [21] . Furthermore, RARα-deficient cells showed enhanced sensitivity to histone deacetylase inhibitors in vitro and in vivo [22] . These studies suggest that retinoid signal activation is necessary for histone deacetylase inhibitor activity.…”

Section: Combination Therapy Improves the Anticancer Activity Of Histmentioning

confidence: 99%

Combination therapies improve the anticancer activities of retinoids in neuroblastoma

Cheung¹

2015

WJCO

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Most therapeutic protocols for child cancers use cytotoxic agents which have a narrow therapeutic index, and resulting in severe acute and chronic toxicities to normal tissues. Despite the fact that most child cancer patients achieve complete remission after chemotherapy, death still occurs due to relapse of persistent minimal residual disease (MRD) which remaining after initial cytotoxic chemotherapy. Advanced neuroblastoma (NB) is a leading cause of cancer deaths in young children. Retinoids are an important component of advanced NB therapy at the stage of MRD, yet half of all patients treated with 13-cis -retinoic acid still relapse and die. More effective combination therapies, with a lower side-effect profile, are required to improve outcomes for NB. Fenretinide or N-4-hydroxyphenyl retinamide is a synthetic derivative of retinoic acid which works on cancer cells through nuclear receptor-dependent and -independent signalling mechanisms. Moreover, several histone deacetylase inhibitors have entered early phase trials, and, suberoylanilide hydroxamic acid has been approved for use in adult cutaneous T cell lymphoma. A number of studies suggest that retinoid signal activation is necessary for histone deacetylase inhibitor activity. A better understanding of their mechanism of actions will lead to more evidence-based retinoid combination therapies. Core tip: Neuroblastoma (NB) begins in embryonal neural crest cells, which later give rise to the sympathetic nervous system, and is caused in part by factors which arrest differentiation. In vitro , retinoids force susceptible cancer cells down a pathway of terminal differentiation and, have been part of the routine treatment of advanced NB for number of decades. Synergistic anti-tumour activity between histone deacetylase inhibitors and retinoids has been observed in a variety of preclinical models. This editorial note discusses some of these findings on the combination therapies for improving the anticancer activities of

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UNC45A Confers Resistance to Histone Deacetylase Inhibitors and Retinoic Acid

Cited by 23 publications

References 27 publications

Dual function of the UNC-45b Chaperone with myosin and GATA4 in cardiac development

Dual function of the UNC-45b Chaperone with myosin and GATA4 in cardiac development

Differential Turnover of Myosin Chaperone UNC-45A Isoforms Increases in Metastatic Human Breast Cancer

Combination therapies improve the anticancer activities of retinoids in neuroblastoma

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