Ectopic expression of testis-specific transcription factor driving lung cancer [RNA-Seq]
The testis-specific BET protein BRDT structurally resembles the ubiquitous BRD4 and is ectopically expressed in various solid tumors, most notably lung cancer. Our analysis of patient samples indicates that BRDT expression may impact lung cancer progression. BRDT knockdown in lung cancer cells slowed tumor growth and prolonged survival in a xenograft model. Comparative characterization of PTEFb complex participation and chromatin binding indicates BRD4-redundant and -distinct BRDT functions. Unlike dual depletion, individual BRD4 or BRDT knockdown did not impair transcriptional responses to hypoxia in BRDT-expressing cells, consistent with redundant function. Acute BRD4 depletion and BRDT complementation revealed that BRDT can also release paused RNA Polymerase II independently of its bromodomains. These results underscore the functional importance of the C-terminal domains present in both BRD4 and BRDT and their potential as therapeutic targets in cancer, particularly in solid tumors. Future investigation will explore BRD4-distinct BRDT functions and BRDT misexpression driving cancer pathogenesis. Overall design: RNA-seq profiling of the NCI-H510 cells, wildtype and their derivatives (sgBRD4 and sgBRDT under hypoxi and normoxic conditions