Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan; Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
Cancer Lett. 2018 Oct 10;434:184-195. doi: 10.1016/j.canlet.2018.07.026. Epub 2018 Jul 21.
GFRA1 and RET are overexpressed in estrogen receptor (ER)-positive breast cancers. Binding of GDNF to GFRA1 triggers RET signaling leading to ER phosphorylation and estrogen-independent transcriptional activation of ER-dependent genes. Both GFRA1 and RET are membrane proteins which are N-glycosylated but no O-linked sialylation site on GFRA1 or RET has been reported. We found GFRA1 to be a substrate of ST3GAL1-mediated O-linked sialylation, which is crucial to GDNF-induced signaling in ER-positive breast cancer cells. Silencing ST3GAL1 in breast cancer cells reduced GDNF-induced phosphorylation of RET, AKT and ERα, as well as GDNF-mediated cell proliferation. Moreover, GDNF induced transcription of ST3GAL1, revealing a positive feedback loop regulating ST3GAL1 and GDNF/GFRA1/RET signaling in breast cancers. Finally, we demonstrated ST3GAL1 knockdown augments anti-cancer efficacy of inhibitors of RET and/or ER. Moreover, high expression of ST3GAL1 was associated with poor clinical outcome in patients with late stage breast cancer and high expression of both ST3GAL1 and GFRA1 adversely impacted outcome in those with high grade tumors.
GFRA1 和 RET 在雌激素受体 (ER) 阳性乳腺癌中过表达。GDNF 与 GFRA1 的结合触发 RET 信号通路，导致 ER 磷酸化和雌激素非依赖性 ER 依赖性基因的转录激活。GFRA1 和 RET 都是膜蛋白，它们都被 N-糖基化，但 GFRA1 或 RET 上没有报道 O-连接唾液酸化位点。我们发现 GFRA1 是 ST3GAL1 介导的 O-连接唾液酸化的底物，这对于 ER 阳性乳腺癌细胞中 GDNF 诱导的信号转导至关重要。在乳腺癌细胞中沉默 ST3GAL1 会降低 GDNF 诱导的 RET、AKT 和 ERα 的磷酸化，以及 GDNF 介导的细胞增殖。此外，GDNF 诱导 ST3GAL1 的转录，揭示了调节乳腺癌中 ST3GAL1 和 GDNF/GFRA1/RET 信号的正反馈回路。最后，我们证明了 ST3GAL1 的敲低增强了 RET 和/或 ER 抑制剂的抗癌疗效。此外，晚期乳腺癌患者中 ST3GAL1 的高表达与不良的临床结局相关，而 ST3GAL1 和 GFRA1 的高表达对高级别肿瘤患者的结局产生不利影响。
