Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, Shanghai, China.
Department of Thoracic Surgery, Shandong Zaozhuang Mining Group Central Hospital, 277800, Zaozhuang, China.
Cell Death Dis. 2021 Dec 1;12(12):1122. doi: 10.1038/s41419-021-04385-1.
Aberrant activation of Wnt/β-catenin signaling and dysregulation of metabolism have been frequently observed in lung cancer. However, the molecular mechanism by which Wnt/β-catenin signaling is regulated and the link between Wnt/β-catenin signaling and cancer metabolism are not fully understood. In this study, we showed that the loss of dual serine/threonine tyrosine protein kinase (DSTYK) led to the activation of Wnt/β-catenin signaling and upregulation of its target gene, lactate dehydrogenase (LDHA), and thus the elevation of lactate. DSTYK phosphorylated the N-terminal domain of β-catenin and inhibited Wnt/β-catenin signaling, which led to the inhibition of cell growth, colony formation and tumorigenesis in a lung adenocarcinoma mouse model. DSTYK was downregulated in lung cancer tissues, and its expression was positively correlated with the survival of patients with lung adenocarcinoma. Taken together, these results demonstrate that the loss of DSTYK activates Wnt/β-catenin/LDHA signaling to promote the tumorigenesis of lung cancer and that DSTYK may be a therapeutic target.
Wnt/β-catenin 信号通路的异常激活和代谢失调在肺癌中经常观察到。然而，Wnt/β-catenin 信号通路的调控机制以及 Wnt/β-catenin 信号通路与癌症代谢之间的联系尚不完全清楚。在这项研究中，我们表明双丝氨酸/苏氨酸酪氨酸蛋白激酶 (DSTYK) 的缺失导致 Wnt/β-catenin 信号通路的激活及其靶基因乳酸脱氢酶 (LDHA) 的上调，从而导致乳酸的升高。DSTYK 磷酸化 β-连环蛋白的 N 端结构域并抑制 Wnt/β-catenin 信号通路，这导致在肺腺癌小鼠模型中细胞生长、集落形成和肿瘤发生的抑制。DSTYK 在肺癌组织中下调，其表达与肺腺癌患者的生存呈正相关。总之，这些结果表明 DSTYK 的缺失激活了 Wnt/β-catenin/LDHA 信号通路，促进了肺癌的肿瘤发生，DSTYK 可能是一个治疗靶点。
