| Autor: |
Webster DE; The Veterans Affairs Palo Alto Healthcare System, Palo Alto, California 94304, USA; The Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA., Barajas B, Bussat RT, Yan KJ, Neela PH, Flockhart RJ, Kovalski J, Zehnder A, Khavari PA |
| Jazyk: |
angličtina |
| Zdroj: |
Genome research [Genome Res] 2014 May; Vol. 24 (5), pp. 751-60. Date of Electronic Publication: 2014 Jan 17. |
| DOI: |
10.1101/gr.166231.113 |
| Abstrakt: |
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 anti-oncogenic functions of a dominant transcription factor and block innate resistance to oncokinase therapy. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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