Abstract
Alternative pre-mRNA splicing (AS) is a biological process that
results in proteomic diversity. However, implications of AS
alterations in cancer remain poorly understood. Herein, we per-
formed a comprehensive AS analysis in cancer driver gene tran-
scripts across fifteen cancer types and found global alterations in
inclusion rates of the PBAF SWI/SNF chromatin remodeling com-
plex subunit Polybromo 1 (PBRM1) exon 27 (E27) in most types of
cancer tissues compared with those in normal tissues. Further
analysis confirmed that PBRM1 E27 is excluded by the direct
binding of RBFOX2 to intronic UGCAUG elements. In addition, the
E27-included PBRM1 isoform upregulated PD-L1 expression via
enhanced PBAF complex recruitment to the PD-L1 promoter.
PBRM1 wild-type patients with clear cell renal cell carcinoma were
resistant to PD-1 blockade therapy when they expressed low
RBFOX2 mRNA levels. Overall, our study suggests targeting of
RBFOX2-mediated AS of PBRM1 as a potential therapeutic strategy
for immune checkpoint blockade.