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

Autor: Gritti I; Massachusetts General Hospital, Boston, United States., Wan J; Massachusetts General Hospital, Boston, MA, United States., Weeresekara V; Massachusetts General Hospital, Boston, United States., Vaz JM; Fred Hutchinson Cancer Center, Seattle, WA, United States., Tarantino G; Dana-Farber Cancer Institute, Boston, Massachussets, United States., Bryde TH; University of Copenhagen, Copenhagen, Denmark., Vijay V; Massachusetts General Hospital, Boston, MA, United States., Kammula AV; Broad Institute, Cambridge, MA, United States., Kattel P; Massachusetts General Hospital, Boston, United States., Zhu S; Fred Hutchinson Cancer Center, Seattle, WA, United States., Vu P; Massachusetts General Hospital Cancer Center, Harvard Medical School, United States., Chan M; Fred Hutchinson Cancer Center, Seattle, WA, United States., Wu MJ; Massachusetts General Hospital, Boston, Massachusetts, United States., Gordan JD; University of California, San Francisco, San Francisco, CA, United States., Patra KC; University of Cincinnati, Cincinnati, OH, United States., Silveira VS; Massachusetts General Hospital, Boston, United States., Manguso RT; Massachusetts General Hospital/Broad Institute, Charlestown, MA, United States., Wein MN; Massachusetts General Hospital, United States., Ott CJ; Massachusetts General Hospital, Boston, MA, United States., Qi J; Dana-Farber Cancer Institute, Boston, MA, United States., Liu D; Dana-Farber Cancer Institute, Boston, MA, United States., Sakamoto K; University of Copenhagen, Copenhagen, Denmark., Gujral TS; Fred Hutchinson Cancer Center, Seattle, WA, United States., Bardeesy N; Massachusetts General Hospital, Boston, United States.
Jazyk: angličtina
Zdroj: Cancer discovery [Cancer Discov] 2024 Sep 27. Date of Electronic Publication: 2024 Sep 27.
DOI: 10.1158/2159-8290.CD-24-0634
Abstrakt: 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.
Databáze: MEDLINE
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