Zhou Bin, Huang Ying, Feng Qian, Zhu Hengqing, Xu Zheng, Chen Leifeng, Peng Xiaogang, Yang Wenlong, Xu Debin, Qiu Yumin
Department of Orthopaedics, The Second Affiliated Hospital of Nanchang University Nanchang 330006, Jiangxi, China.
Department of Rehabilitation Medicine, The Second Affiliated Hospital of Nanchang University Nanchang 330006, Jiangxi, China.
Am J Cancer Res. 2022 Nov 15;12(11):5205-5225. eCollection 2022.
Enhanced aerobic glycolysis contributes to the metastasis of pancreatic cancer metastasis, but the mechanism underlying the abnormal activation of glycolysis has not been fully elucidated. The E3 ligase tripartite motif 16 (TRIM16) is involved in the progression of many cancers. However, the role of and molecular mechanism by which TRIM16 acts in pancreatic cancer are unclear. In this study, we report that TRIM16 was significantly upregulated in pancreatic cancer tissues, and high expression of TRIM16 was associated with poor prognosis in patients with pancreatic cancer. Multivariate analyses showed that TRIM16 was an independent predictor of poor outcomes among patients with pancreatic cancer. In addition, and evidence showed that TRIM16 promoted pancreatic cancer cell metastasis by enhancing glycolysis. Furthermore, we revealed that TRIM16 controlled glycolysis and pancreatic cancer cell's metastasis by regulating sine oculis homeobox 1 (SIX1), an important transcription factor that promotes glycolysis. TRIM16 upregulated SIX1 by inhibiting its ubiquitination and degradation, which was mediated by NF-κB-inducing kinase (NIK), an upstream regulator of SIX1. Hence, NIK inhibitor can suppress SIX1 expression, glycolysis and metastasis in TRIM16-overexpressing pancreatic cancer cells. Mechanistic investigations demonstrated that TRIM16 competed with NIK's E3 ligase, TNF receptor-associated factor 3 (TRAF3), at the ISIIAQA sequence motif of NIK, and then stabilized NIK protein. Our study identified the TRIM16-NIK-SIX1 axis as a critical regulatory pathway in aerobic glycolysis and pancreatic cancer metastasis, indicating that this axis can be an excellent therapeutic target for curing pancreatic cancer.
有氧糖酵解增强促进胰腺癌转移，但其糖酵解异常激活的机制尚未完全阐明。E3 连接酶三联基序 16（TRIM16）参与多种癌症的进展。然而，TRIM16 在胰腺癌中的作用及其分子机制尚不清楚。在本研究中，我们发现 TRIM16 在胰腺癌组织中显著上调，且 TRIM16 的高表达与胰腺癌患者的不良预后相关。多变量分析表明，TRIM16 是胰腺癌患者不良预后的独立预测因子。此外，有证据表明 TRIM16 通过增强糖酵解促进胰腺癌细胞转移。此外，我们还发现 TRIM16 通过调节促进糖酵解的重要转录因子眼无同源框 1（SIX1）来控制糖酵解和胰腺癌细胞转移。TRIM16 通过抑制由 SIX1 的上游调节因子 NF-κB 诱导激酶（NIK）介导的 SIX1 的泛素化和降解来上调 SIX1。因此，NIK 抑制剂可抑制 TRIM16 过表达的胰腺癌细胞中 SIX1 的表达、糖酵解和转移。机制研究表明，TRIM16 在 NIK 的 ISIIAQA 序列基序处与 NIK 的 E3 连接酶肿瘤坏死因子受体相关因子 3（TRAF3）竞争，从而稳定 NIK 蛋白。我们的研究确定了 TRIM16-NIK-SIX1 轴是有氧糖酵解和胰腺癌转移中的关键调节途径，表明该轴可能是治疗胰腺癌的理想靶点。
