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Axing the cancer loop

Completion of the sequencing of the human genome and the annotation of its variation across populations has provided powerful resources for biomedical research. Efforts are still needed to identify and functionally characterize DNA elements that regulate gene expression and influence variations of traits and disease susceptibility. To address this need, large collections of putative disease and trait-associated genomic loci as well as non-coding distal regulatory elements are being identified through evolutionary, biochemical, and genetic experimental approaches (Kellis et al., 2014). The non-coding DNA elements being identified can influence gene expression through a variety of mechanisms. One mechanism is operating as enhancers of target genes via chromatin looping, which is the juxtapositioning of distal regulatory elements with the promoter or transcription start site (TSS) of a gene. This results in bringing the noncoding element into closer physical proximity to the TSS as intervening sequences often occur over large genomic distances. Underlying enhancer chromatin loop organization is the recruitment and assembly of master transcription factors at enhancer DNA sequences (Whyte et al., 2013). In the melanocyte-lineage, for example, putative enhancers are enriched with DNA sequence motifs matching the binding sites for the lineage-specific master transcription factors SOX10 and MITF (Gorkin et al., 2012) consistent with the notion that enhancer binding modulates chromatin looping and cell-specific gene expression. However, whether melanocyte-lineage master transcription factors directly mediate chromatin looping and whether targeting enhancer chromatin loops offers cancer-specific therapeutic effects are not fully understood. One of the hallmarks of cancer is sustaining proliferative signaling through activating mutations and/or amplified expression of genes encoding oncogenic proteins (Hanahan and Weinberg, 2011). Oncogenic protein kinases (oncokinases) such as EGFR, ALK, ERBB2, and BRAF are capable of driving constitutive signaling to other oncogenic pathways, often involving the mitogen-activated protein kinase (MAPK) and the phosphoinositide 3-kinase (PI3K) (Straussman et al., 2012). Pharmacological inhibition of oncokinases is widely used in cancer treatment to block oncogene-induced tumor cell proliferation. Unfortunately, cancer cells often evolve unique abilities to evade the antiproliferative effects of inhibitory drugs. In multiple cancer types, oncokinase inhibition is associated with the secretion of the hepatocyte growth factor (HGF) by the tumor stroma and the upregulation of the HGF receptor, MET (Straussman et al., 2012). HGF signaling to MET downstream of oncokinase inhibition leads to the re-activation of the MAPKand PI3K-signaling pathways, thus creating an alternative tumor survival mechanism that dampens the antitumorigenic effects of therapeutic drugs. A longstanding question is how cancers of various cell-lineages sense pharmacological inhibition of oncokinases at the genomic level and elicit an innate resistance response. In a paper recently published in Genome Research, Webster et al. (2014) provide compelling evidence to conclude that a drug-inducible, melanocytelineage-specific enhancer chromatin loop at the MET locus upregulates MET expression and mediates innate drug resistance response to oncokinase inhibition in melanoma. Webster et al. (2014) began by systematically investigating the genomic regulatory landscape of the MET gene using the publicly available DNase I hypersensitive sites (DHSs) dataset from The ENCyclopedia Of DNA Elements (ENCODE) project. Through unsupervised hierarchical clustering of DHSs data from 100 cell types, Webster et al. (2014) discovered multiple-cell-lineagespecific DHSs clusters surrounding the MET locus suggestive of a chromatin domain harboring enhancer-like gene regulatory elements. Remarkably, the largest DHSs cluster within the MET locus was found in the melanocyte lineage and located 63 kb downstream of the TSS of the MET gene (MET +63 kb). Further, in vitro analysis of the MET +63 kb DHSs cluster for enhancer activity demonstrated transcriptional activation exclusively in the melanocyte lineage in both primary and melanoma cells but not in cell lines derived from non-melanocyte lineages. These initial observations underscored the likelihood of a melanocyte-lineage-specific enhancer within the MET +63 kb sequence. Webster et al. (2014) hypothesized that the MET +63 kb enhancer mediates MET gene upregulation in response to oncokinase inhibition in melanoma. To test this possibility, the authors made use of the melanoma cell line COLO829 that harbors a constitutively active V600E amino acid-mutated BRAF kinase (BRAF), and the drug PLX4032 (vemurafenib) that selectively inhibits BRAF. PLX4032 treatment of COLO829 melanoma cells upregulated the expression of the MET gene and increased the activity of the MET +63 kb enhancer. To determine whether MET +63 kb enhancer activity and the upregulation of MET are linked, Webster et al. (2014) performed chromosome conformation capture (3C) assay, a tool that detects evidence of chromatin looping between two DNA fragments. Upon PLX4032 treatment of melanoma cells, the interaction between the MET +63 kb enhancer and MET TSS