Kolliopoulos Constantinos, Chatzopoulos Athanasios, Skandalis Spyros S, Heldin Carl-Henrik, Heldin Paraskevi
Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden.
Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece.
Cancers (Basel). 2021 Mar 1;13(5):1021. doi: 10.3390/cancers13051021.
The hyaluronan receptor CD44 can undergo proteolytic cleavage in two steps, leading to the release of its intracellular domain; this domain is translocated to the nucleus, where it affects the transcription of target genes. We report that CD44 cleavage in A549 lung cancer cells and other cells is promoted by transforming growth factor-beta (TGFβ) in a manner that is dependent on ubiquitin ligase tumor necrosis factor receptor-associated factor 4 or 6 (TRAF4 or TRAF6, respectively). Stem-like A549 cells grown in spheres displayed increased TRAF4-dependent expression of CD44 variant isoforms, CD44 cleavage, and hyaluronan synthesis. Mechanistically, TRAF4 activated the small GTPase RAC1. CD44-dependent migration of A549 cells was inhibited by siRNA-mediated knockdown of TRAF4, which was rescued by the transfection of a constitutively active RAC1 mutant. Our findings support the notion that TRAF4/6 mediates pro-tumorigenic effects of CD44, and suggests that inhibitors of CD44 signaling via TRAF4/6 and RAC1 may be beneficial in the treatment of tumor patients.
透明质酸受体CD44可经历两步蛋白水解切割，导致其细胞内结构域释放；该结构域易位至细胞核，在细胞核中影响靶基因的转录。我们报告称，在A549肺癌细胞和其他细胞中，转化生长因子-β（TGFβ）以依赖泛素连接酶肿瘤坏死因子受体相关因子4或6（分别为TRAF4或TRAF6）的方式促进CD44切割。在球体中生长的干细胞样A549细胞表现出TRAF4依赖性的CD44变异体亚型表达增加、CD44切割和透明质酸合成。从机制上讲，TRAF4激活了小GTP酶RAC1。通过siRNA介导的TRAF4敲低抑制了A549细胞的CD44依赖性迁移，而组成型活性RAC1突变体的转染挽救了这种抑制作用。我们的研究结果支持TRAF4/6介导CD44的促肿瘤作用这一观点，并表明通过TRAF4/6和RAC1抑制CD44信号传导可能对肿瘤患者的治疗有益。
