Cancer Discov. 2024 Sep 27.
Ilaria Gritti,
Jinkai Wan,
Vajira Weeresekara,
Joel M Vaz,
Giuseppe Tarantino,
Tenna Holgersen Bryde,
Vindhya Vijay,
Ashwin V Kammula,
Prabhat Kattel,
Songli Zhu,
Phuong Vu,
Marina Chan,
Meng-Ju Wu,
John D Gordan,
Krushna C Patra,
Vanessa S Silveira,
Robert T Manguso,
Marc N Wein,
Christopher J Ott,
Jun Qi,
David Liu,
Kei Sakamoto,
Taranjit S Gujral,
Nabeel Bardeesy.
Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples. We show that a core function of DNAJB1-PRKACA is the phosphorylation and inactivation of Salt-inducible kinases (SIKs). This leads to deregulation of the CRTC2 transcriptional co-activator and p300 acetyltransferase, resulting in transcriptional reprogramming and increased global histone acetylation, driving malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest the potential of targeting CRTC2/p300 in FLC. Notably, these findings link this rare cancer's signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression.