纤维板层癌 (FLC) 是一种青少年和年轻人的肝癌，其特征是编码蛋白激酶 A 催化亚基 PRKACA 和热休克蛋白 DNAJB1 的基因融合。嵌合 DNAJB1-PRKACA 蛋白具有增加的激酶活性，对于 FLC 异种移植物生长至关重要。在这里，我们使用源自患者的 FLC 模型、工程系统和患者样本探索 DNAJB1-PRKACA 控制的关键致癌途径。我们证明 DNAJB1-PRKACA 的核心功能是盐诱导激酶 (SIK) 的磷酸化和失活。这导致 CRTC2 转录共激活因子和 p300 乙酰转移酶失调，导致转录重编程和整体组蛋白乙酰化增加，从而驱动恶性生长。我们的研究建立了 DNAJB1-PRKACA 的核心致癌机制，并表明在 FLC 中靶向 CRTC2/p300 的潜力。值得注意的是，这些发现将这种罕见癌症的标志性融合癌蛋白与涉及 STK11 和 GNAS 的更常见癌症基因改变联系起来，这些基因改变也通过 SIK 抑制发挥作用。

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.