Mutant KRAS and CK2 Cooperatively Stimulate SLC16A3 Activity to Drive Intrahepatic Cholangiocarcinoma Progression
Ran Chen, Cuihong Ma, Haoran Qian, Xinyu Xie, Yuxue Zhang, Dayun Lu, Shunjie Hu, Mao Zhang, Fen Liu, Yanmei Zou, Qiang Gao, Hu Zhou, Hailong Liu, Moubin Lin, Gaoxiang Ge, Daming Gao
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignancy affecting the liver and biliary system. Enhanced understanding of the pathogenic mechanisms underlying iCCA tumorigenesis and the discovery of appropriate therapeutic targets are imperative to improve patient outcomes. In this study, we investigated the functions and regulations of solute carrier family 16 member 3 (SLC16A3), which has been reported to be a biomarker of poor prognosis in iCCA. High SLC16A3 expression was enriched in KRAS viral oncogene homolog-mutated iCCA tumors, and mutant KRAS elevated SLC16A3 expression via the PI3K-AKT-mTORC1-HIF1α pathway. SLC16A3 not only enhanced glycolysis but also induced epigenetic reprogramming to regulate iCCA progression. Phosphorylation of SLC16A3 at S436 was vital for its oncogenic function and was linked to iCCA progression. Casein kinase 2 (CK2) directly phosphorylated SLC16A3 at S436, and CK2 inhibition with CX-4945 (silmitasertib) reduced the growth of KRAS-mutated iCCA tumor xenografts and patient-derived organoids. Together, this study provides valuable insights into the diverse functions of SLC16A3 in iCCA and comprehensively elucidates the upstream regulatory mechanisms, providing potential therapeutic strategies for patients with iCCA with KRAS mutations. Significance: Characterization of the oncogenic function and regulators of SLC16A3 in intrahepatic cholangiocarcinogenesis revealed the potential of CK2 inhibitors as a promising treatment for KRAS-mutated tumors.