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A renal cancer-associated, renal tubule-specific, HIF-binding enhancer of oncogenic MYC and PVT1 expression

ABSTRACT: Clear cell renal cell carcinoma is characterized by loss of function of the von Hippel-Lindau tumor suppressor gene (VHL) and unrestrained activation of hypoxia inducible transcription factors (HIF). Genetic and epigenetic determinants can impact on HIF pathways. A recent genome-wide association study identified single nucleotide polymorphisms (SNPs) in an intergenic region on chromosome 8 that modify the risk of developing renal cancer. The SNPs are located in a putative regulatory region between the oncogenes MYC and PVT1. Using capture C assay and genome editing we show that HIF-binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins. Moreover, we demonstrate that the risk associated polymorphisms increase chromatin accessibility and activity as well as binding of HIF to the enhancer. These findings further strengthen the hypothesis that genetic variation at HIF-binding sites modulates the oncogenic transcriptional output of the VHL-HIF axis and provide a functional explanation for disease associated effects of SNPs in ccRCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE84444 | GEO | 2017/02/12

SECONDARY ACCESSION(S): PRJNA329187

REPOSITORIES: GEO

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Project description:Renal cancer accounts for 2% to 3% of all adult malignancies in the US. In 2011 more than 64,770 new cases and 13,000 deaths were reported and the incidence is steadily increasing by 2.5% per year. Clear cell renal carcinoma (ccRCC) represents the majority (85% to 90%) of adult kidney cancers and is the most malignant. This cancer is characterized by an early loss of the von Hippel-Lindau tumor suppressor (VHL) on short arm of chromosome 3 in the majority of tumors (80%). It is a classic knowledge that loss of VHL results in an increased accumulation and activity of the hypoxia-inducible transcription factor (HIF), which in turns activates expression of genes promoting tumor growth. In that respect, induction of angiogenic factors induces blood flow through the tumors and delivery of nutrients and oxygen to cancer cells, while induction of genes inducing anaerobic glycolysis supports adaptation to reduced nutrients availability and shifts towards metabolic pathways promoting tumor growth. Recently we have discovered another tumor suppressing pathway regulated by VHL. We found that VHL is a major regulator of the process of macroautophagy (autophagy) (ref). We identified that VHL induces expression of a microRNA, miR-204, which in turn inhibits activity of a major regulator required for the formation of autophagosome, LC3B. LC3B-mediated autophagy is necessary for the ccRCC tumor growth, and inhibition of this process by VHL and miR-204 significantly contributes to the tumor suppression. Most importantly, we discovered that VHL by inhibiting activity of HIF, induced expression and activity of an LC3B paralog, LC3C. In contrast to LC3B, LC3C acts as a tumor suppressor, indicating the specificity and complexity of different autophagic programs. Integrating these novel data with the established role of VHL in regulating angiogenesis produces a more global picture of VHL as a master tumor suppressor that regulates nutrient access for renal cancer cells from both extracellular and intracellular sources. In the process of searching for other genes induced by VHL that could participate in the tumor suppressing activity of VHL, we discovered that reconstitution of VHL in RCC cells induces enrichment of genes expressed from the Smith-Magenis locus (SM), located on the short arm of chromosome 17p11.2. Smith-Magenis syndrome is a complex neurobehevioural disorder, characterized by intellectual impairment, craniofacial and skeletal anomalies and sleep disturbance. Recently, deletions or mutations of one specific gene in the SM locus, RAI1, (retinoic acid induced 1), were shown to be responsible for the syndrome. Interestingly, this locus contains another kidney tumor suppressor gene, folliculin (FLCN), of which activity is lost in the genetic dominant disorder, Birt-Hogg-Dube syndrome (BHD). BHD is characterized by skin fibrofolliculomas, pulmonary cysts and spontaneous pneumothorax, as well as renal cancer of mixed histological types, including chromophobe, oncocytic, clear cell and papillary type. Here we show that VHL regulates expression of FLCN, and in turn FLCN contributes to the VHL-mediated suppression of tumor growth. Two-condition experiment, VHL(-) vs. VHL(+). 4 biological replicates in each group. Two dual-channel arrays with VHL(+) on Cy5 and VHL(-) on Cy3, and two dual-channel arrays with flipped samples.

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A renal cancer-associated, renal tubule-specific, HIF-binding enhancer of oncogenic MYC and PVT1 expression

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