RRM2 gene expression depends on BAF180 subunit of SWISNF chromatin remodeling complex and correlates with abundance of tumor infiltrating lymphocytes in ccRCC

About 40% of clear cell renal cell carcinoma (ccRCC) cases carry the mutation inactivating BAF180 subunit of the SWI/SNF chromatin remodeling complex (CRC). Here we show that the majority of transcriptomic changes appear at the stage I of ccRCC development. By contrast, the stage II ccRCC exhibits hyperactivation of DNA replication demonstrated by the overexpression of several genes, e.g., and genes encoding subunits of ribonucleotide reductase (RNR) complex. We found that the degree of and upregulation in ccRCC patients depends on mutation. We show that the BAF180 protein product of the gene directly binds to and . The BAF180 binding regions are targeted by regulatory proteins previously reported as SWI/SNF CRC interacting partners. BAF180 binding to correlates with enrichment of H3K27me3 in case of and H3K14Ac on , indicating the existence of differential regulatory mechanism controlling expression of these genes. We found that the strong overexpression of RRM2 in ccRCC patient samples correlates with T cell infiltration. Surprisingly, the majority of tumor infiltrating lymphocytes (TILs) consisted of CD4 T cells. Furthermore, we show that exhausted CD4 T cells induced the expression of the gene in the primary ccRCC cell line. Collectively, our results provide the link between loss, RRM2 expression and T cell infiltration, which may lead to the establishment of new treatment of this disease.