Up-regulation of MET Expression by α-Melanocyte-stimulating Hormone and MITF Allows Hepatocyte Growth Factor to Protect Melanocytes and Melanoma Cells from Apoptosis

Beuret, Laurent; Flori, Enrica; Denoyelle, Christophe; Bille, Karine; Buscà, Roser; Picardo, Mauro; Bertolotto, Corine; Ballotti, Robert

doi:10.1074/jbc.m611563200

Cited by 77 publications

(82 citation statements)

References 39 publications

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“…2B). While MYC ChIPseq peaks were the most enriched feature for this analysis, we prioritized MITF due to its role as a master regulator (Steingrímsson et al 2004;Levy et al 2006), lineage-specific oncogene (Garraway et al 2005;Tsao et al 2012), and its association with MET regulation (McGill et al 2006;Beuret et al 2007) and enhancer function (Gorkin et al 2012). These results raised the possibility that MITF may utilize lineage-specific regulatory elements to control MET expression in melanoma downstream from BRAF inhibition.…”

Section: Resultsmentioning

confidence: 99%

Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition

et al. 2014

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Thousands of putative enhancers are characterized in the human genome, yet few have been shown to have a functional role in cancer progression. Inhibiting oncokinases, such as EGFR, ALK, ERBB2, and BRAF, is a mainstay of current cancer therapy but is hindered by innate drug resistance mediated by up-regulation of the HGF receptor, MET. The mechanisms mediating such genomic responses to targeted therapy are unknown. Here, we identify lineage-specific enhancers at the MET locus for multiple common tumor types, including a melanoma lineage-specific enhancer 63 kb downstream from the MET TSS. This enhancer displays inducible chromatin looping with the MET promoter to up-regulate MET expression upon BRAF inhibition. Epigenomic analysis demonstrated that the melanocyte-specific transcription factor, MITF, mediates this enhancer function. Targeted genomic deletion (<7 bp) of the MITF motif within the MET enhancer suppressed inducible chromatin looping and innate drug resistance, while maintaining MITF-dependent, inhibitor-induced melanoma cell differentiation. Epigenomic analysis can thus guide functional disruption of regulatory DNA to decouple pro-and antioncogenic functions of a dominant transcription factor and block innate resistance to oncokinase therapy.

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Section: Resultsmentioning

confidence: 99%

Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition

et al. 2014

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“…Treatment of melanocytes with cAMP-elevating agents has previously been shown to result in increased MITF expression (43), as well as up-regulation of target genes with somewhat paradoxically opposing functions. On one hand, cAMP pathway stimulation of MITF activity in melanocytes up-regulates the expression of hypoxia-inducible factor 1a (HIF1a) and the hepatocytye growth factor receptor MET, which promote cell survival (44,45). On the flip side, MITF also upregulates the inhibitors of cell cycle progression, p21 CIP1 and p16…”

Section: Discussionmentioning

confidence: 99%

Microphthalmia-Associated Transcription Factor Is a Critical Transcriptional Regulator of Melanoma Inhibitor of Apoptosis in Melanomas

Dynek¹,

Chan

Liu

et al. 2008

Cancer Research

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Melanoma inhibitor of apoptosis (ML-IAP) is a potent inhibitor of apoptosis, which is highly expressed in melanomas and likely contributes to their resistance to chemotherapeutic treatments. Herein, we show that the lineage survival oncogene microphthalmia-associated transcription factor (MITF) is a critical regulator of ML-IAP transcription in melanoma cells. The ML-IAP promoter contains two MITF consensus sites, and analysis of MITF and ML-IAP mRNA levels revealed a high correlation in melanoma tumor samples and cell lines. In reporter assays, MITF promoted a strong stimulation of transcriptional activity from the ML-IAP promoter, and MITF bound the endogenous ML-IAP promoter in melanoma cells by chromatin immunoprecipitation and electrophoretic mobility shift assay. Strikingly, small interfering RNA (siRNA)-mediated knockdown of MITF in melanoma cells led to a dramatic decrease in ML-IAP mRNA and protein levels, establishing that ML-IAP expression in melanoma cells is MITF dependent. Additionally, cyclic AMP-mediated induction of MITF expression in melanocytes resulted in increased ML-IAP expression, suggesting that melanocytes can express ML-IAP when MITF levels are heightened. Disruption of MITF by siRNA led to a decrease in melanoma cell viability, which could be rescued by ectopic expression of ML-IAP. Collectively, these findings implicate MITF as a major transcriptional regulator of ML-IAP expression in melanomas, and suggest that ML-IAP contributes to the prosurvival activity of MITF in melanoma progression. [Cancer Res 2008;68(9):3124-32]

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“…Other Q-PCR were performed exactly as described. 36 Cell viability test. Cell viability was assessed using the Cell Proliferation Kit II (XTT; Roche Diagnostics, Meylan, France) according to the manufacturer's protocol.…”

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confidence: 99%

Ciglitazone negatively regulates CXCL1 signaling through MITF to suppress melanoma growth

et al. 2010

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We have previously demonstrated that the thiazolidinedione ciglitazone inhibited, independently of PPARc activation, melanoma cell growth. Further investigations now show that ciglitazone effects are mediated through the regulation of secreted factors. Q-PCR screening of several genes involved in melanoma biology reveals that ciglitazone inhibits expression of the CXCL1 chemokine gene. CXCL1 is overexpressed in melanoma and contributes to tumorigenicity. We show that ciglitazone induces a diminution of CXCL1 level in different human melanoma cell lines. This effect is mediated by the downregulation of microphthalmia-associated transcription factor, MITF, the master gene in melanocyte differentiation and involved in melanoma development. Further, recombinant CXCL1 protein is sufficient to abrogate thiazolidinedione effects such as apoptosis induction, whereas extinction of the CXCL1 pathway mimics phenotypic changes observed in response to ciglitazone. Finally, inhibition of human melanoma tumor development in nude mice treated with ciglitazone is associated with a strong decrease in MITF and CXCL1 levels. Our results show that anti-melanoma effects of thiazolidinediones involve an inhibition of the MITF/ CXCL1 axis and highlight the key role of this specific pathway in melanoma malignancy. Cell Death and Differentiation (2011) 18, 109-121; doi:10.1038/cdd.2010.75; published online 2 July 2010Cutaneous melanoma is an aggressive skin cancer that originates from epidermal melanocytes. Melanoma development is accomplished through the accumulation of genetic alterations in growth control pathways including oncogenic mutations or gene amplification. For example, constitutive activation of the Ras/MAPkinase-signaling pathway is frequently observed in melanomas, as a consequence of activating mutations of the B-Raf and N-Ras genes. 1-3Melanoma progression is also accompanied by generation of autocrine and paracrine loops associated with the aberrant production and secretion of growth factors and chemokines that sustain growth, survival and invasion. 4 In humans, melanoma is one of the most lethal cancers among young adults. Melanoma has a high capability of invasion and rapid metastasis to other organs. The prognosis of metastatic melanoma is extremely dismal, as the various treatments have not shown survival benefit.5 It appears thus necessary to develop approaches enabling the discovery of new molecular targets, candidates for specific biotherapy treatment of this disease.Thiazolidinediones (TZDs) regulate transcriptional activity of the nuclear receptor peroxysome proliferator activated receptor g (PPARg) and are currently used in type II diabetes treatment. More recently, TZD have been reported to inhibit proliferation and survival of numerous cancer cells. 6 Furthermore, we have previously demonstrated that ciglitazone, which belongs to TZD family, inhibits growth and viability of melanoma cells without affecting normal melanocyte growth. 7To further investigate the molecular events elicited by ciglitazone and to b...

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Up-regulation of MET Expression by α-Melanocyte-stimulating Hormone and MITF Allows Hepatocyte Growth Factor to Protect Melanocytes and Melanoma Cells from Apoptosis

Cited by 77 publications

References 39 publications

Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition

Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition

Microphthalmia-Associated Transcription Factor Is a Critical Transcriptional Regulator of Melanoma Inhibitor of Apoptosis in Melanomas

Ciglitazone negatively regulates CXCL1 signaling through MITF to suppress melanoma growth

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