Abstract
A subset of clear cell renal cell carcinoma (ccRCC) tumors exhibit a HIF1A gene mutation, yielding two ccRCC tumor types, H1H2 type expressing both HIF1α and HIF2α, and H2 type expressing HIF2α, but not functional HIF1α protein. However, it is unclear how the H1H2 type ccRCC tumors escape HIF1’s tumor-suppressive activity. The polybromo-1 (PBRM1) gene coding for the BAF180 protein, a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, is inactivated in 40% ccRCCs, the function and mechanism of BAF180 mutation is unknown. Our previous study indicates that BAF180-containing SWI/SNF chromatin remodeling complex is a co-activator for transcription factor HIF to induce HIF target genes. Thus, our questions are if BAF180 is involved in HIF-mediated hypoxia response and if PBRM1/BAF180 mutation has any association with the HIF1A retention in H1H2 type ccRCC. We report here that BAF180 is mutated in H1H2 ccRCC cell lines and tumors, and BAF180 re-expression in H1H2 ccRCC cell lines reduced cell proliferation/survival, indicating that BAF180 has tumor-suppressive role in these cells. However, BAF180 is expressed in HIF1-deficient H2 ccRCC cell lines and tumors, and BAF180 knockdown in H2 type ccRCC cell lines reduced cell proliferation/survival, indicating that BAF180 has tumor-promoting activity in these cells. In addition, our data show that BAF180 functions as co-activator for HIF1- and HIF2-mediated transcriptional response, and BAF180’s tumor-suppressive and -promoting activity in ccRCC cell lines depends on co-expression of HIF1 and HIF2, respectively. Thus, our studies reveal that BAF180 function in ccRCC is context dependent, and that mutation of PBRM1/BAF180 serves as an alternative strategy for ccRCC tumors to reduce HIF1 tumor-suppressive activity in H1H2 ccRCC tumors. Our studies define distinct functional subgroups of ccRCCs based on expression of BAF180, and suggest that BAF180 inhibition may be a novel therapeutic target for patients with H2, but not H1H2, ccRCC tumors.
Highlights
The incidence of kidney cancers has continued to rise, with 62 000 new cases and over 14 000 deaths predicted to occur in 2016 in the United States.[1]
Despite positive role of both HIF1 and HIF2 in clear cell renal cell carcinomas (ccRCC) initiation, results from clinical and laboratory studies indicate that HIF2 plays a positive role in ccRCC tumor maintenance,[19,20,21] whereas HIF1 has a tumor-suppressive role in late stage ccRCC development and in established ccRCC tumors
The goal of this study was to determine if PBRM1/BAF180 is important for HIF1- and HIF2-mediated transcriptional response, and if the BAF180 gene mutation is associated with HIF1A retention in H1H2 ccRCC, a tumorsuppressive factor in established ccRCC tumors
Summary
The incidence of kidney cancers has continued to rise, with 62 000 new cases and over 14 000 deaths predicted to occur in 2016 in the United States.[1]. Despite the significant structural similarities of HIF1α and HIF2α proteins, and their common co-factor, ARNT, HIF1 and HIF2 regulate unique, as well as common target genes.[16,17] it is not surprising that both HIF1A and HIF2A gene are required for the ccRCC tumor development/initiation in a mouse model, in which both VHL and TP53 are knocked out in renal tubule epithelial cells.[18] Despite positive role of both HIF1 and HIF2 in ccRCC initiation, results from clinical and laboratory studies indicate that HIF2 plays a positive role in ccRCC tumor maintenance,[19,20,21] whereas HIF1 has a tumor-suppressive role in late stage ccRCC development and in established ccRCC tumors. On the basis of the expression pattern of HIF1α, ccRCC tumors can be divided into two subtypes: H2 ccRCC tumors that express HIF2α but not a functional HIF1α protein, and H1H2 ccRCC tumors that express both HIF1α and HIF2α protein.[2,22] Given the evidence that HIF1 functions as a tumor suppressor, an important question that has not been addressed is how H1H2 ccRCC tumors tolerate HIF1α protein expression
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