HOXC6 Is Deregulated in Human Head and Neck Squamous Cell Carcinoma and Modulates Bcl-2 Expression

Moon, Sungmin; Kim, Soo‐A; Yoon, Jung‐Hoon; Ahn, Sang‐Gun

doi:10.1074/jbc.m112.361675

Cited by 41 publications

(50 citation statements)

References 41 publications

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“…S8B-C). HOXC genes (important for anti-apoptotic pathway [27, 28]) were downregulated at the early time point (Fig. S8D) in line with H23 cells undergoing apoptosis and slower cell proliferation rate (Figure 5(b)).…”

Section: Resultsmentioning

confidence: 69%

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Handoko¹,

Kaczkowski²,

Hon³

et al. 2018

Epigenetics

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The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found that a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and -independent manner.

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Section: Resultsmentioning

confidence: 69%

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Handoko¹,

Kaczkowski²,

Hon³

et al. 2018

Epigenetics

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“…These analysis showed that overexpression of HOXC6 (Flag-HOXC6) resulted in upregulation of VEGF (vascular epithelial growth factor), bFGF (basic fribroblast growth factor), and PDGFRA (platelate derived growth factor receptor-alpha) (Figure 8D). VEGF, bFGF and PDGFRA are well known tumor grwoth factors what are over expressed in variety tumors and contribute towards tumor growth, angiogenesis, and metastasis (23, 24, 27, 31, 36–38, 79, 80). Theorefore, the upregulation of these tumor growth factor upon overexpression of HOXC6 indicate potential roles of HOXC6 in tumor cell proliferation and growth.…”

Section: Resultsmentioning

confidence: 99%

“…HOXC6 expression is associated with several human carcinomas such as cancers of gastrointestinal, breast, lung, prostate, head and neck squamous cell carcinomas, osteosarcomas, medulloblastomas and leukemias (15, 19, 21, 24, 25, 28, 29, 81). HOXC6 is also transcriptionally upregulated in lymph node metastases (31). HOXC6 regulates the expression of various tumor growth factors such as connective tissue growth factor (CTGF), T-cell receptor alternate reading frame protein (TARP), insulin-like growth factor binding protein 3 (IGFBP3), and neutral endopeptidase/membrane metallo-endopeptidase (NEP/MME) and therefore contribute to tumorigenesis (24, 30, 80).…”

Section: Discussionmentioning

confidence: 99%

“…HOXC6 overexpression has been detected in variety of cancers including breast (15, 21), lung (25) prostate (26), leukemia (27), osteosarcomas (28), and medulloblastomas (29). HOXC6 regulates proteins such as bone morphogenic protein 7 (BMP7), fibroblast growth factor receptor 2 (FGFR2), and platelet-derived growth factor receptor α (PDGFRA) that are crucial players in tumor cell proliferation, growth, and metastasis (30, 31). It also regulates the PI3K/Akt, Notch, and Wnt signaling pathways (30–35).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Bisphenol-A induces expression of HOXC6, an estrogen-regulated homeobox-containing gene associated with breast cancer

Hussain

Bhan

Ansari

et al. 2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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HOXC6 is a homeobox-containing gene associated with mammary gland development and is overexpressed in variety of cancers including breast and prostate cancers. Here, we have examined the expression of HOXC6 in breast cancer tissue, investigated its transcriptional regulation via estradiol (E2) and bisphenol-A (BPA, an estrogenic endocrine disruptor) in vitro and in vivo. We observed that HOXC6 is differentially over-expressed in breast cancer tissue. E2 induces HOXC6 expression in cultured breast cancer cells and in mammary glands of Sprague Dawley rats. HOXC6 expression is also induced upon exposure to BPA both in vitro and in vivo. Estrogen-receptor-alpha (ERα) and ER-coregulators such as MLL-histone methylases are bound to the HOXC6 promoter upon exposure to E2 or BPA and that resulted in increased histone H3K4-trimethylation, histone acetylation, and recruitment of RNA polymerase II at the HOXC6 promoter. HOXC6 overexpression induces expression of tumor growth factors and facilitates growth 3D-colony formation, indicating its potential roles in tumor growth. Our studies demonstrate that HOXC6, which is a critical player in mammary gland development, is upregulated in multiple cases of breast cancer, and is transcriptionally regulated by E2 and BPA, in vitro and in vivo.

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“…These results imply a role for Otx2 as a key regulator of genes that are essential for the function and identity of these cells, such that they fail to survive without them, or the direct regulation by Otx2 of anti-apoptotic genes. The latter function has recently been demonstrated for a variety of homeobox and paired-type homeobox transcription factors (Ninkovic et al, 2010;Fuchs et al, 2012;Moon et al, 2012).…”

Section: Otx2 As a Master Regulator Of Chp Development And Maintenancementioning

confidence: 89%

The transcription factor Otx2 regulates choroid plexus development and function

et al. 2013

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SUMMARYThe choroid plexuses (ChPs) are the main regulators of cerebrospinal fluid (CSF) composition and thereby also control the composition of a principal source of signaling molecules that is in direct contact with neural stem cells in the developing brain. The regulators of ChP development mediating the acquisition of a fate that differs from the neighboring neuroepithelial cells are poorly understood. Here, we demonstrate in mice a crucial role for the transcription factor Otx2 in the development and maintenance of ChP cells. Deletion of Otx2 by the Otx2-CreERT2 driver line at E9 resulted in a lack of all ChPs, whereas deletion by the Gdf7-Cre driver line affected predominately the hindbrain ChP, which was reduced in size, primarily owing to an increase in apoptosis upon Otx2 deletion. Strikingly, Otx2 was still required for the maintenance of hindbrain ChP cells at later stages when Otx2 deletion was induced at E15, demonstrating a central role of Otx2 in ChP development and maintenance. Moreover, the predominant defects in the hindbrain ChP mediated by Gdf7-Cre deletion of Otx2 revealed its key role in regulating early CSF composition, which was altered in protein content, including the levels of Wnt4 and the Wnt modulator Tgm2. Accordingly, proliferation and Wnt signaling levels were increased in the distant cerebral cortex, suggesting a role of the hindbrain ChP in regulating CSF composition, including key signaling molecules. Thus, Otx2 acts as a master regulator of ChP development, thereby influencing one of the principal sources of signaling in the developing brain, the CSF.

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HOXC6 Is Deregulated in Human Head and Neck Squamous Cell Carcinoma and Modulates Bcl-2 Expression

Cited by 41 publications

References 41 publications

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Bisphenol-A induces expression of HOXC6, an estrogen-regulated homeobox-containing gene associated with breast cancer

The transcription factor Otx2 regulates choroid plexus development and function

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