Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, China.
NHC Key Laboratory of Pulmonary Immune-related Diseases, Guizhou Provincial People's Hospital, Guiyang 550002, China.
Int J Biol Sci. 2022 Jan 24;18(4):1539-1554. doi: 10.7150/ijbs.67842. eCollection 2022.
Hyperactivation of Wnt/β-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the mechanisms underlying the hyperactivation of Wnt/β-catenin signaling are incompletely understood. In this study, Pantothenate kinase 1 (PANK1) is shown to be a negative regulator of Wnt/β-catenin signaling. Downregulation of PANK1 in HCC correlates with clinical features. Knockdown of PANK1 promotes the proliferation, growth and invasion of HCC cells, while overexpression of PANK1 inhibits the proliferation, growth, invasion and tumorigenicity of HCC cells. Mechanistically, PANK1 binds to CK1α, exerts protein kinase activity and cooperates with CK1α to phosphorylate N-terminal serine and threonine residues in β-catenin both in vitro and in vivo. Additionally, the expression levels of PANK1 and β-catenin can be used to predict the prognosis of HCC. Collectively, the results of this study highlight the crucial roles of PANK1 protein kinase activity in inhibiting Wnt/β-catenin signaling, suggesting that PANK1 is a potential therapeutic target for HCC.
Wnt/β-catenin 信号通路的过度激活已在肝细胞癌（HCC）中被报道。然而，Wnt/β-catenin 信号通路过度激活的机制尚未完全阐明。在这项研究中，发现泛酸激酶 1（PANK1）是 Wnt/β-catenin 信号通路的负调控因子。PANK1 在 HCC 中的下调与临床特征相关。PANK1 的敲低促进 HCC 细胞的增殖、生长和侵袭，而过表达 PANK1 则抑制 HCC 细胞的增殖、生长、侵袭和致瘤性。在机制上，PANK1 与 CK1α 结合，发挥蛋白激酶活性，并与 CK1α 合作，在体外和体内磷酸化 β-catenin 的 N 端丝氨酸和苏氨酸残基。此外，PANK1 和 β-catenin 的表达水平可用于预测 HCC 的预后。总之，这项研究的结果强调了 PANK1 蛋白激酶活性在抑制 Wnt/β-catenin 信号通路中的关键作用，表明 PANK1 是 HCC 的一个潜在治疗靶点。
