Role of PBRM1 in regulation of the HIF pathway

Abstract

Hypoxia Inducible Factors are a family of transcription factors mediating the transcriptional response to hypoxia. They are heterodimers consisting of an oxygen-regulated α subunit and an oxygen-independent β subunit. In normoxia HIFα is quickly degraded by a VHL-mediated mechanism whereas hypoxia stabilizes this subunit making it available to form an active complex and induce transcription of its target genes. Recently, it was shown that the SWI/SNF chromatin remodeling complex plays an important role in HIF transcriptional responses. SWI/SNF is a large multiprotein complex composed of at least 15 subunits. PBRM1 is a distinctive subunit of the PBAF subcomplex of SWI/SNF that was recently found to be mutated in different cancer types such as pancreatic, breast, and renal. Interestingly, PBRM1 and VHL are the most frequently mutated genes in clear cell Renal Cell Carcinoma (ccRCC). Mutations or loss of VHL leads to upregulation of both HIF1α and HIF2α. However, recent studies indicate that HIF1α and HIF2α play opposing roles in renal cancer progression: HIF1α is a tumour suppressor whereas HIF2α acts an oncogene. Here, it is shown that PBRM1 is able to selectively regulate the expression of HIF1α in a BRG1-independent manner. PBRM1 is important for recognition of HIF1α mRNA by YTHDF2 and able to interact with mRNA suggesting a link between this chromatin remodeling complex and mRNA processing. Additionally, PBRM1 contributes to the hypoxia induced expression of HK2 and PHD2 genes, possibly by interacting with HIF1 at HRE sites in the promoters of these genes.

Date of Award	2016
Original language	English
Sponsors	Wellcome Trust
Supervisor	Sonia Rocha (Supervisor)