Constitutive GLI1 expression in chondrosarcoma is regulated by major vault protein via mTOR/S6K1 signaling cascade.
Constitutive GLI1 expression in chondrosarcoma is regulated by major vault protein via mTOR/S6K1 signaling cascade.
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DOI：
10.1038/s41418-021-00749-4
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发表时间：
2021-07
影响因子：
12.4
通讯作者：
Ren T
中科院分区：
文献类型：
--
作者：
Wang W;Yan T;Guo W;Niu J;Zhao Z;Sun K;Zhang H;Yu Y;Ren T
Hedgehog信号在胚胎模式的形成和出生后生物过程的不同方面发挥着关键作用。Hedgehog途径的干扰和Hedgehog途径下游转录因子GLI1的过度表达与包括软骨肉瘤(CS)在内的几种恶性肿瘤密切相关。我们先前发现，下调GLI1的表达可以减弱中断的印度刺猬(IHH)信号通路，并抑制人CS细胞的存活。然而，调控GLI1表达的潜在机制仍不清楚。在这里，我们论证了GLI1在CS细胞SMO非依赖性通路中的意义。用亲和纯化方法鉴定了GLI1结合蛋白--主要vault蛋白(MVP)。MVP通过降低GLI1与融合同源抑制物(SuFU)的结合亲和力，并通过mTOR/S6K1信号通路增加GLI1的表达，从而促进GLI1的核转运和稳定。在功能上，MVP的敲除抑制了细胞的生长并诱导了细胞的凋亡。同时抑制MVP和GLI1对CS的生长有明显的抑制作用。免疫组化结果显示，MVP、GLI1、P-p70S6K1在71例人CS组织中均有高表达，且三者之间呈正相关。总体而言，我们的发现揭示了一种新的调节HH非依赖性GLI1表达的机制，并为晚期CS患者的联合治疗提供了理论基础。
Hedgehog signaling plays a pivotal role in embryonic pattern formation and diverse aspects of the postnatal biological process. Perturbation of the hedgehog pathway and overexpression of GLI1, a downstream transcription factor in the hedgehog pathway, are highly relevant to several malignancies including chondrosarcoma (CS). We previously found that knocking down expression of GLI1 attenuates the disrupted Indian hedgehog (IHH) signal pathway and suppresses cell survival in human CS cells. However, the underlying mechanisms regulating the expression of GLI1 are still unknown. Here, we demonstrated the implication of GLI1 in SMO-independent pathways in CS cells. A GLI1 binding protein, major vault protein (MVP), was identified using the affinity purification method. MVP promoted the nuclear transport and stabilization of GLI1 by compromising the binding affinity of GLI1 with suppressor of fused homolog (SUFU) and increased GLI1 expression via mTOR/S6K1 signaling cascade. Functionally, knockdown of MVP suppressed cell growth and induced apoptosis. Simultaneous inhibition of MVP and GLI1 strongly inhibits the growth of CS in vitro and in vivo. Moreover, IHC results showed that MVP, GLI1, and P-p70S6K1 were highly expressed and positively correlated with each other in 71 human CS tissues. Overall, our findings revealed a novel regulating mechanism for HH-independent GLI1 expression and provide a rationale for combination therapy in patients with advanced CS.
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影响因子：
4.8
作者：
Kolli, S;Zito, CI;Bennett, AM
通讯作者：
Bennett, AM
影响因子：
2.9
作者：
Barnfield, PC;Zhang, XY;Hui, CC
通讯作者：
Hui, CC
DOI：
10.1007/s004280050201
发表时间：
1998-06-01
期刊：
VIRCHOWS ARCHIV-AN INTERNATIONAL JOURNAL OF PATHOLOGY
影响因子：
--
作者：
Chano, T;Okabe, H;Hukuda, S
通讯作者：
Hukuda, S
HCC 中去甲基化诱导的 Shc3 过度表达驱动 MEK/ERK 的 c-Raf 独立激活
影响因子：
11.2
作者：
Liu, Yun;Zhang, Xinran;Zhang, Ning
通讯作者：
Zhang, Ning
影响因子：
5.4
作者：
Kim, E;Lee, S;Suh, PG
通讯作者：
Suh, PG