DNAJB1-PRKACA fusion drives fibrolamellar liver cancer through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming

Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults defined by fusion of the DNAJB1 heat shock protein and protein kinase A (PKA) catalytic subunit (DNAJB1-PRKACA). The resulting chimeric protein has increased kinase activity and is essential for FLC xenograft growth. However, the critical oncogenic pathways controlled by DNAJB1-PRKACA have not been defined. Here, we explored this question by studying patient-derived FLC models and engineered systems and analyzing patient samples. We show that the core function of DNAJB1-PRKACA is the direct phosphorylation and inactivation of the Salt-inducible kinases. This leads to deregulation of the CRTC2 co-activator and p300 acetyltransferase, resulting in transcriptional reprogramming and global increases in histone acetylation necessary for malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest opportunities for therapeutic targeting of CRTC2/p300 in FLC. Notably, these findings link this signature fusion oncoprotein of a rare cancer type to more common cancer gene alterations involving the STK11 tumor suppressor and GNAS oncogene, which also function via SIK suppression.