DEAH-BOX HELICASE 8 IS A REGULATOR OF HEAT SHOCK FACTOR 1

Heat Shock Factor 1 (HSF1) is a key transcription factor mediating the cellular stress response and promoting cancer cell survival. We identify DEAH-box helicase 8 (DHX8) as a crucial regulator of HSF1 pre-mRNA processing. Silencing DHX8 leads to the accumulation of HSF1 transcripts with retained introns and reduced HSF1 protein. Intron retention is also detected in canonical heat shock and cancer-signature gene sets regulated by HSF1, and in mitosis, G2M checkpoint, cMYC and E2F-associated gene sets. Consistent with intron retention and the role DHX8 in the later stages of splicing, eCLIP analysis finds significant enrichment of DHX8 binding between the lariat branch site and 3’ splice junction. DHX8 silencing induces apoptosis in cancer cells to a greater extent than in non-tumorigenic cells. We show that the ATPase activity of DHX8 is essential for function, and propose DHX8 as a therapeutic target on pathways that protect cancer cells from oncogene-induced stress.