Department of Biochemistry, School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China.
Cell Biol Int. 2021 Nov;45(11):2251-2263. doi: 10.1002/cbin.11673. Epub 2021 Jul 29.
Caveolin-1 (CAV1), a major structural protein of caveolae, is reported to exert a positive regulatory effect on tumor growth and to play a crucial role in hepatocellular carcinoma (HCC) cell metastasis by regulating glycosyltransferase expression and cellular glycosylation. However, the role of CAV1 in modulating protein glycosylation and tumor metastasis remains to be further elucidated. In the present study, we showed that CAV1 promoted the expression of O-GlcNAc transferase (OGT), which catalyzed the addition of O-GlcNAc residues to a variety of nuclear and cytoplasmic proteins. In human HCC cell lines with different metastatic potentials, high levels of OGT and cellular O-GlcNAcylation were associated with CAV1 expression and cell metastasis. Overexpression of CAV1 increased the levels of OGT and O-GlcNAcylation, and cell migration was also increased. Furthermore, CAV1 was found to reduce the expression of Runt-related transcription factor 2 (RUNX2) in HCC cells. Subsequently, this effect resulted in the attenuation of the RUNX2-induced transcription of microRNA24 (miR24), a microRNA previously shown to suppress OGT mRNA expression by targeting its 3' untranslated regions (UTR). Finally, we demonstrated that CAV1 induced cellular O-GlcNAcylation and HCC cell invasion. This study provides evidence of CAV1-mediated increases in OGT expression and O-GlcNAcylation. These data provide insight into a novel mechanism underlying HCC metastasis and suggest a novel strategy for the treatment of HCC.
窖蛋白-1（CAV1）是质膜窖（caveolae）的主要结构蛋白，据报道，它通过调节糖基转移酶的表达和细胞糖基化，对肿瘤生长发挥正向调节作用，并在肝细胞癌（HCC）细胞转移中发挥关键作用。然而，CAV1 调节蛋白质糖基化和肿瘤转移的作用仍有待进一步阐明。在本研究中，我们表明 CAV1 促进了 O-连接 N-乙酰氨基葡萄糖转移酶（OGT）的表达，OGT 催化将 O-连接 N-乙酰氨基葡萄糖残基添加到各种核和细胞质蛋白中。在具有不同转移潜能的人 HCC 细胞系中，高表达的 OGT 和细胞内 O-连接 N-乙酰氨基葡萄糖化与 CAV1 表达和细胞转移相关。CAV1 的过表达增加了 OGT 和 O-连接 N-乙酰氨基葡萄糖化的水平，并且细胞迁移也增加了。此外，CAV1 被发现降低了 HCC 细胞中 runt 相关转录因子 2（RUNX2）的表达。随后，这种效应导致 RUNX2 诱导的 microRNA24（miR24）转录减弱，miR24 先前被证明通过靶向其 3'非翻译区（UTR）来抑制 OGT mRNA 表达。最后，我们证明 CAV1 诱导细胞内 O-连接 N-乙酰氨基葡萄糖化和 HCC 细胞侵袭。本研究提供了 CAV1 介导的 OGT 表达和 O-连接 N-乙酰氨基葡萄糖化增加的证据。这些数据为 HCC 转移的新机制提供了依据，并为 HCC 的治疗提供了新策略。
