PDF(Pubmed)
Abstract：
Accumulating evidence has shown that H6 Family Homeobox 3 (HMX3) plays a crucial role in nervous system regulation. However, the regulatory mechanism of HMX3 in colorectal cancer (CRC) has seldom been studied. Herein, HMX3 was significantly downregulated in CRC, as demonstrated by qRT-PCR and WB analysis on clinical samples and a panel of cell lines. Besides, it was found that the expression of HMX3 was negatively correlated with survival of CRC patients. The functional analyses (EdU staining, CCK-8, colony formation, Transwell, and wound scratch assays) showed that CRC cell proliferation, migration, and invasion were significantly suppressed by HMX3 overexpression, while enhanced by HMX3 knockdown. Moreover, in vivo experiment revealed HMX3 overexpression could also suppress tumor growth. Combining bioinformatics and WB analysis, we preliminarily uncovered that HMX3 was involved in apoptosis and KRAS signaling pathways. Mechanistically, Ubiquitin-specific protease 38 (USP38) was identified as a novel post-translational regulator of HMX3, which could directly interact with HMX3 to stabilize its protein expression via deubiquitination. Furthermore, the role of USP38 silencing in promoting cell proliferation, migration, and invasion of CRC cells was blocked by HMX3 overexpression. In conclusion, our findings suggested that USP38/HMX3 axis is a novel promising therapeutic candidate for CRC.
摘要：
越来越多的证据表明，H6家族同源异型盒3（HMX3）在神经系统调节中起着至关重要的作用。然而,HMX3在结直肠癌(CRC)中的调控机制研究较少。在这里，HMX3在CRC中显著下调，如通过对临床样品和一组细胞系的qRT-PCR和WB分析所证明的。此外,发现HMX3的表达与CRC患者的生存率呈负相关。功能分析(EdU染色，CCK-8,集落形成,Transwell,和伤口划痕分析)显示CRC细胞增殖，迁移,HMX3过表达显著抑制侵袭，同时通过HMX3敲低增强。此外，体内实验显示HMX3过表达也可抑制肿瘤生长。结合生物信息学和WB分析，我们初步发现HMX3参与细胞凋亡和KRAS信号通路。机械上,泛素特异性蛋白酶38（USP38）被鉴定为HMX3的新型翻译后调节因子，可以直接与HMX3相互作用，通过去泛素化稳定其蛋白表达。此外，USP38沉默在促进细胞增殖中的作用，迁移,HMX3过表达阻断了CRC细胞的侵袭。总之,我们的研究结果表明,USP38/HMX3轴是一种新的有前景的CRC治疗候选物.
