Divergent roles of HDAC1 and HDAC2 in the regulation of epidermal development and tumorigenesis

Winter, Mircea; Moser, M.; Meunier, Dominique; Fischer, Carina; Machat, Georg; Mattes, Katharina; Lichtenberger, Beate M.; Brunmeir, Reinhard; Weissmann, Simon; Murko, Christina; Humer, Christina; Meischel, Tina; Brosch, Gerald; Matthias, Patrick; Sibilia, Maria; Seiser, Christian

doi:10.1038/emboj.2013.243

Cited by 60 publications

(59 citation statements)

References 53 publications

(98 reference statements)

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“…Whereas the effect of HDAC inhibitors used in the treatment of solid tumours are disappointing 43,44 , it has also been shown that HDAC inhibitors can induce EMT in prostate cancer cells 45 . HDAC1 and HDAC2 have been reportedly shown to function as tumour suppressors in epidermis and lymphomas [46][47][48] . In this study, we also showed that HDAC1 is a negative regulator of Smad2 and Smad3.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis

et al. 2015

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Altered transforming growth factor-b (TGF-b) signalling has been implicated in tumour development and progression. However, the molecular mechanism behind this alteration is poorly understood. Here we show that profilin-2 (Pfn2) increases Smad2 and Smad3 expression via an epigenetic mechanism, and that profilin-2 and Smad expression correlate with an unfavourable prognosis of lung cancer patients. Profilin-2 overexpression promotes, whereas profilin-2 knockdown drastically reduces, lung cancer growth and metastasis. We show that profilin-2 suppresses the recruitment of HDAC1 to Smad2 and Smad3 promoters by preventing nuclear translocation of HDAC1 through protein-protein interaction at the C terminus of both proteins, leading to the transcriptional activation of Smad2 and Smad3. Increased Smad2 and Smad3 expression enhances TGF-b1-induced EMT and production of the angiogenic factors VEGF and CTGF. These findings reveal a new regulatory mechanism of TGF-b1/Smad signalling, and suggest a potential molecular target for the development of anticancer drugs.

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Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis

et al. 2015

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“…Indeed, Hdac1 and Hdac2 redundantly regulate various cellular and developmental processes, including cardiac morphogenesis, adipogenesis, brain development, intestinal homeostasis, proliferation, and stem-cell self-renewal (Montgomery et al, 2007; Montgomery et al, 2009; Haberland et al, 2010; Jurkin et al, 2011; Jamaladdin et al, 2014; Zimberlin et al, 2015). In some cases, a single allele of Hdac1 or Hdac2 is enough to rescue the double knockout phenotype (Dovey et al, 2013; Winter et al, 2013; Hagelkruys et al, 2014). While the developmental roles of Hdac1 and Hdac2 are emerging, their function in NC progenitor cells remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase 1 and 2 are essential for murine neural crest proliferation, pharyngeal arch development, and craniofacial morphogenesis

Milstone

Lawson

Trivedi

2017

Developmental Dynamics

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Background Craniofacial anomalies involve defective pharyngeal arch development and neural crest function. Copy number variation at 1p35, containing histone deacetylase 1 (Hdac1), or 6q21-22, containing Hdac2, are implicated in patients with craniofacial defects, suggesting an important role in guiding neural crest development. However, the roles of Hdac1 and Hdac2 within neural crest cells remain unknown. Results The neural crest and its derivatives express both Hdac1 and Hdac2 during early murine development. Ablation of Hdac1 and Hdac2 within murine neural crest progenitor cells cause severe hemorrhage, atrophic pharyngeal arches, defective head morphogenesis, and complete embryonic lethality. Embryos lacking Hdac1 and Hdac2 in the neural crest exhibit decreased proliferation and increased apoptosis in both the neural tube and the first pharyngeal arch. Mechanistically, loss of Hdac1 and Hdac2 upregulates cyclin-dependent kinase inhibitors Cdkn1a, Cdkn1b, Cdkn1c, Cdkn2b, Cdkn2c, and Tp53 within the first pharyngeal arch. Conclusions Our results show that Hdac1 and Hdac2 function redundantly within the neural crest to regulate proliferation and the development of the pharyngeal arches via repression of cyclin-dependent kinase inhibitors.

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“…However, the safety of the HDAC inhibitors is a significant concern because HDAC1 and HDAC2 also play important roles in regulating gene expression in development. Loss of HDAC1 and HDAC2 led to profound defects in tissues with epithelial structures, such as intestine and epidermis (Brunmeir et al, 2009; Gonneaud et al, 2015; Winter et al, 2013). Furthermore, the enzymatic activities of HDAC1 and HDAC2 are dependent on their incorporation into different protein complexes, such as the Sin3, NuRD and CoREST complexes, which bind and deacetylate distinct substrates (Kelly and Cowley, 2013; Moser et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Loss of histone deacetylase HDAC1 induces cell death in Drosophila epithelial cells through JNK and Hippo signaling

Zhang

Sheng

2016

Mechanisms of Development

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Inactivation of HDAC1 and its homolog HDAC2 or addition of HDAC inhibitors in mammalian systems induces apoptosis, cell cycle arrest, and developmental defects. Although these phenotypes have been extensively characterized, the precise underlying mechanisms remain unclear, particularly in in vivo settings. In this study, we show that inactivation of Rpd3, the only HDAC1 and HDAC2 ortholog in Drosophila, induced apoptosis and clone elimination in the developing eye and wing imaginal discs. Depletion of Rpd3 by RNAi cell-autonomously increased JNK activities and decreased activities of Yki, the nuclear effecter of Hippo signaling pathway. In addition, inhibition of JNK activities largely rescued Rpd3 RNAi-induced apoptosis, but did not affect its inhibition of Yki activities. Conversely, increasing the Yki activities largely rescued Rpd3 RNAi-induced apoptosis, but did not affect its induction of JNK activities. Furthermore, inactivation of Mi-2, a core component of the Rpd3-containing NuRD complex strongly induced JNK activities; while inactivation of Sin3A, a key component of the Rpd3-containing Sin3 complex, significantly inhibited Yki activities. Taken together, these results reveal that inactivation of Rpd3 independently regulates JNK and Yki activities and that both Hippo and JNK signaling pathways contribute to Rpd3 RNAi-induced apoptosis.

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Divergent roles of HDAC1 and HDAC2 in the regulation of epidermal development and tumorigenesis

Cited by 60 publications

References 53 publications

Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis

Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis

Histone deacetylase 1 and 2 are essential for murine neural crest proliferation, pharyngeal arch development, and craniofacial morphogenesis

Loss of histone deacetylase HDAC1 induces cell death in Drosophila epithelial cells through JNK and Hippo signaling

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