PDF(Pubmed)
Abstract：
While deubiquitinase ATXN3 has been implicated as a potential oncogene in various types of human cancers, its role in colon adenocarcinoma remains understudied. Surprisingly, our findings demonstrate that ATXN3 exerts an antitumor effect in human colon cancers through potentiating Galectin-9-induced apoptosis. CRISPR-mediated ATXN3 deletion unexpectedly intensified colon cancer growth both in vitro and in xenograft colon cancers. At the molecular level, we identified ATXN3 as a bona fide deubiquitinase specifically targeting Galectin-9, as ATXN3 interacted with and inhibited Galectin-9 ubiquitination. Consequently, targeted ATXN3 ablation resulted in reduced Galectin-9 protein expression, thereby diminishing Galectin-9-induced colon cancer apoptosis and cell growth arrest. The ectopic expression of Galectin-9 fully reversed the growth of ATXN3-null colon cancer in mice. Furthermore, immunohistochemistry staining revealed a significant reduction in both ATXN3 and Galectin-9 protein expression, along with a positive correlation between them in human colon cancer. Our study identifies the first Galectin-9-specific deubiquitinase and unveils a tumor-suppressive role of ATXN3 in human colon cancer.
摘要：
虽然去泛素酶ATXN3被认为是各种类型人类癌症的潜在癌基因，其在结肠腺癌中的作用仍未得到充分研究。令人惊讶的是,我们的发现表明ATXN3通过增强Galectin-9诱导的细胞凋亡在人结肠癌中发挥抗肿瘤作用.CRISPR介导的ATXN3缺失意外地增强了体外和异种移植结肠癌的结肠癌生长。在分子水平上,我们将ATXN3鉴定为特异性靶向半乳糖凝集素-9的真正的去泛素酶,因为ATXN3与半乳糖凝集素-9相互作用并抑制其泛素化.因此,靶向ATXN3消融导致半乳糖凝集素-9蛋白表达减少，从而减少Galectin-9诱导的结肠癌细胞凋亡和细胞生长停滞。Galectin-9的异位表达完全逆转了小鼠中ATXN3无效结肠癌的生长。此外，免疫组织化学染色显示ATXN3和Galectin-9蛋白表达显著降低,以及它们在人类结肠癌中的正相关。我们的研究确定了第一个半乳糖凝集素-9特异性去泛素酶，并揭示了ATXN3在人类结肠癌中的肿瘤抑制作用。
