Yi Haisheng, Liu Lingyun, Zhang Jingshun, Guo Kaimin, Cao Yin, Sun Penghao, Wang Hongliang
Department of Andrology, The First Hospital of Jilin University, Changchun, 130012, China.
Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, 130041, China.
Discov Oncol. 2024 Mar 13;15(1):73. doi: 10.1007/s12672-024-00930-4.
Polypeptide N-Acetylgalactosaminyltransferase (GALNTs) are critical enzymes that initiate mucin type-O glycosylation, and are closely associated with the occurrence and development of multiple cancers. However, the significance of GALNT2 in clear cell renal cell carcinoma (ccRCC) progression remains largely undetermined. Based on public multi-omics analysis, GALNT2 was strongly elevated in ccRCC versus adjoining nontumor tissues, and it displayed a relationship with poor overall survival (OS) of ccRCC patients. In addition, GALNT2 over-expression accelerated proliferation of renal cancer cell (RCC) lines. In contrast, GALNT2 knockdown using shRNAs suppressed cell proliferation, and this was rescued by LATS2 knockdown. Similarly, GALNT2 deficiency enhanced p-LATS2/LATS2 expression. LATS2 is activated by phosphorylation (p-LATS2) and, in turn, phosphorylate the downstream substrate protein YAP. Phosphorylated YAP (p-YAP) stimulated its degradation and cytoplasmic retention, as it was unable to translocate to the nucleus. This resulted in reduced cell proliferation. Subsequently, we explored the upstream miRNAs of GALNT2. Using dual luciferase reporter assay, we revealed that miR-139-5p interacted with the 3' UTR of GALNT2. Low miR-139-5p expression was associated with worse ccRCC patient outcome. Based on our experiments, miR-139-5p overexpression inhibited RCC proliferation, and this phenotype was rescued by GALNT2 overexpression. Given these evidences, the miR-139-5p-GALNT2-LATS2 axis is critical for RCC proliferation, and it is an excellent candidate for a new therapeutic target in ccRCC.
多肽N-乙酰半乳糖胺基转移酶（GALNTs）是启动粘蛋白O型糖基化的关键酶，与多种癌症的发生和发展密切相关。然而，GALNT2在透明细胞肾细胞癌（ccRCC）进展中的意义仍 largely未确定。基于公共多组学分析，与相邻的非肿瘤组织相比，GALNT2在ccRCC中显著升高，并且它与ccRCC患者较差的总生存期（OS）相关。此外，GALNT2过表达加速了肾癌细胞（RCC）系的增殖。相反，使用shRNAs敲低GALNT2可抑制细胞增殖，而这种抑制作用可通过敲低LATS2来挽救。同样，GALNT2缺陷增强了p-LATS2/LATS2的表达。LATS2通过磷酸化（p-LATS2）被激活，进而磷酸化下游底物蛋白YAP。磷酸化的YAP（p-YAP）刺激其降解并使其滞留在细胞质中，因为它无法转运到细胞核。这导致细胞增殖减少。随后，我们探索了GALNT2的上游miRNAs。使用双荧光素酶报告基因测定法，我们发现miR-139-5p与GALNT2的3'UTR相互作用。低miR-139-5p表达与ccRCC患者更差的预后相关。基于我们的实验，miR-139-5p过表达抑制RCC增殖，而GALNT2过表达可挽救这种表型。鉴于这些证据，miR-139-5p-GALNT2-LATS2轴对RCC增殖至关重要，并且它是ccRCC新治疗靶点的优秀候选者。
