ArticleCancer research2024
Increased Protein Kinase A Activity Induces Fibrolamellar Hepatocellular Carcinoma Features Independent of DNAJB1.
Article in Cancer research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Fibrolamellar Carcinoma in the Molecular Era: From DNAJB1::PRKACA Biology to Precision Therapeutic Strategies.Journal of gastrointestinal cancer · 2026Review
- Clinical guideline for the diagnosis and treatment of fibrolamellar carcinoma.Hepatology (Baltimore, Md.) · 2026Article
- Article
- Functional Precision Oncology in Fibrolamellar Carcinoma: Ex Vivo Identification of Therapeutic Vulnerabilities.Cancers · 2026Article
- Single-nucleus ATAC-seq analysis resolves chromatin and transcriptional features of fibrolamellar carcinoma.Scientific reports · 2026Article
- FusionCancers · 2026Article
- Global Re-Analysis Confirms Absence of theCancers · 2026Article
- Putative Imprinting Control Regions with Aberrant Blood-Based DNA Methylation are Associated with Hepatocellular Carcinoma Risk.Journal of hepatocellular carcinoma · 2026Article
- Metastatic Fibrolamellar Hepatocellular Carcinoma in a Young Adult: A Case Report and Narrative Review.Journal of hepatocellular carcinoma · 2026Article
- Article
- cAMP promotes acute lysosome biogenesis through TFEB nuclear import-export dynamics.bioRxiv : the preprint server for biology · 2025Article
- Liver cancer multiomics reveals diverse protein kinase A disruptions convergently produce fibrolamellar hepatocellular carcinoma.Nature communications · 2024Article
- A network frame offers a promising transdisciplinary tool for understanding complex health and health care system problems like suicide.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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Authors and funding
18 authors.
Funding
Abstract
Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver cancer that is driven by the fusion of DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). PKA activity is controlled through regulatory proteins that both inhibit catalytic activity and control localization, and an excess of regulatory subunits ensures PRKACA activity is inhibited. Here, we found an increase in the ratio of catalytic to regulatory units in FLC patient tumors driven by DNAJB1::PRKACA using mass spectrometry, biochemistry, and immunofluorescence, with increased nuclear localization of the kinase. Overexpression of DNAJB1::PRKACA, ATP1B1::PRKACA, or PRKACA, but not catalytically inactive kinase, caused similar transcriptomic changes in primary human hepatocytes, recapitulating the changes observed in FLC. Consistently, tumors in patients missing a regulatory subunit or harboring an ATP1B1::PRKACA fusion were indistinguishable from FLC based on the histopathological, transcriptomic, and drug-response profiles. Together, these findings indicate that the DNAJB1 domain of DNAJB1::PRKACA is not required for FLC. Instead, changes in PKA activity and localization determine the FLC phenotype. Significance: Alterations leading to unconstrained protein kinase A signaling, regardless of the presence or absence of PRKACA fusions, drive the phenotypes of fibrolamellar hepatocellular carcinoma, reshaping understanding of the pathogenesis of this rare liver cancer.
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