MRC Cancer Cell Unit, Hutchison-MRC Research centre, Addenbrooke's Hospital Cambridge, UK.
Exp Cell Res. 2013 Jan 1;319(1):103-12. doi: 10.1016/j.yexcr.2012.08.010. Epub 2012 Sep 14.
HES6, a member of the hairy-enhancer-of-split family of transcription factors, plays multiple roles in myogenesis. It is a direct target of the myogenic transcription factor MyoD and has been shown to regulate the formation of the myotome in development, myoblast cell cycle exit and the organization of the actin cytoskeleton during terminal differentiation. Here we investigate the expression and function of HES6 in rhabdomyosarcoma, a soft tissue tumor which expresses myogenic genes but fails to differentiate into muscle. We show that HES6 is expressed at high levels in the subset of alveolar rhabdomyosarcomas expressing PAX/FOXO1 fusion genes (ARMSp). Knockdown of HES6 mRNA in the ARMSp cell line RH30 reduces proliferation and cell motility. This phenotype is rescued by expression of mouse Hes6 which is insensitive to HES6 siRNA. Furthermore, expression microarray analysis indicates that the HES6 knockdown is associated with a decrease in the levels of Transgelin, (TAGLN), a regulator of the actin cytoskeleton. Knockdown of TAGLN decreases cell motility, whilst TAGLN overexpression rescues the motility defect resulting from HES6 knockdown. These findings indicate HES6 contributes to the pathogenesis of ARMSp by enhancing both proliferation and cell motility.
HES6 是 hairy-enhancer-of-split 家族转录因子的成员，在肌发生中发挥多种作用。它是肌源性转录因子 MyoD 的直接靶标，已被证明可调节发育中的体节形成、成肌细胞细胞周期退出以及终末分化过程中肌动蛋白细胞骨架的组织。在这里，我们研究了 HES6 在横纹肌肉瘤中的表达和功能，横纹肌肉瘤是一种表达肌源性基因但不能分化为肌肉的软组织肿瘤。我们发现 HES6 在表达 PAX/FOXO1 融合基因的肺泡横纹肌肉瘤亚组中高表达 (ARMSp)。在 ARMSp 细胞系 RH30 中敲低 HES6 mRNA 会降低增殖和细胞迁移能力。这种表型可以通过表达对 HES6 siRNA 不敏感的小鼠 Hes6 来挽救。此外，表达微阵列分析表明，HES6 敲低与肌动蛋白细胞骨架调节剂 Transgelin（TAGLN）水平降低有关。TAGLN 的敲低会降低细胞迁移能力，而 TAGLN 的过表达则可以挽救由于 HES6 敲低导致的迁移缺陷。这些发现表明 HES6 通过增强增殖和细胞迁移来促进 ARMSp 的发病机制。
