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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 coactivator 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\u2019s signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>This work combines functional studies in model systems and examination of human tumor specimens to define a central oncogenic pathway driven by DNAJB1-PRKACA fusions in FLC. DNAJB1-PRKACA-mediated inactivation of the SIK stimulates CRTC2-p300-mediated transcription to drive tumor growth. The findings illuminate pathogenic mechanisms and inform therapeutic development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-0634","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T17:39:56Z","timestamp":1727372396000},"page":"382-400","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["DNAJB1-PRKACA Fusion Drives Fibrolamellar Liver Cancer through Impaired SIK Signaling and CRTC2\/p300-Mediated Transcriptional Reprogramming"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7313-0450","authenticated-orcid":false,"given":"Ilaria","family":"Gritti","sequence":"first","affiliation":[{"name":"1Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts."},{"name":"2Center for Cancer Research, Center for Regenerative Medicine, Massachusetts General, Boston, Massachusetts."},{"name":"3Department of Medicine, Harvard Medical School, Boston, Massachusetts."},{"name":"4Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6736-0332","authenticated-orcid":false,"given":"Jinkai","family":"Wan","sequence":"additional","affiliation":[{"name":"1Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts."},{"name":"2Center for Cancer Research, Center for Regenerative Medicine, Massachusetts General, Boston, Massachusetts."},{"name":"3Department of Medicine, Harvard Medical School, Boston, Massachusetts."},{"name":"4Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9668-7091","authenticated-orcid":false,"given":"Vajira","family":"Weeresekara","sequence":"additional","affiliation":[{"name":"1Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts."},{"name":"2Center for Cancer Research, Center for Regenerative Medicine, Massachusetts General, Boston, Massachusetts."},{"name":"3Department of Medicine, Harvard Medical School, Boston, Massachusetts."},{"name":"4Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7177-3525","authenticated-orcid":false,"given":"Joel M.","family":"Vaz","sequence":"additional","affiliation":[{"name":"5Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, 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