Chai Jian Yi, Sugumar Vaisnevee, Alshawsh Mohammed Abdullah, Wong Won Fen, Arya Aditya, Chong Pei Pei, Looi Chung Yeng
School of Biosciences, Faculty of Health & Medical Sciences, Taylor's University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia.
School of Medicine, Faculty of Health & Medical Sciences, Taylor's University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia.
Biomedicines. 2021 Sep 10;9(9):1188. doi: 10.3390/biomedicines9091188.
The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved among mammals, with crucial roles in regulating embryonic development as well as in cancer initiation and progression. The GLI transcription factors (GLI1, GLI2, and GLI3) are effectors of the Hh pathway and are regulated via Smoothened (SMO)-dependent and SMO-independent mechanisms. The SMO-dependent route involves the common Hh-PTCH-SMO axis, and mutations or transcriptional and epigenetic dysregulation at these levels lead to the constitutive activation of GLI transcription factors. Conversely, the SMO-independent route involves the SMO bypass regulation of GLI transcription factors by external signaling pathways and their interacting proteins or by epigenetic and transcriptional regulation of GLI transcription factors expression. Both routes of GLI activation, when dysregulated, have been heavily implicated in tumorigenesis of many known cancers, making them important targets for cancer treatment. Hence, this review describes the various SMO-dependent and SMO-independent routes of GLI regulation in the tumorigenesis of multiple cancers in order to provide a holistic view of the paradigms of hedgehog signaling networks involving GLI regulation. An in-depth understanding of the complex interplay between GLI and various signaling elements could help inspire new therapeutic breakthroughs for the treatment of Hh-GLI-dependent cancers in the future. Lastly, we have presented an up-to-date summary of the latest findings concerning the use of Hh inhibitors in clinical developmental studies and discussed the challenges, perspectives, and possible directions regarding the use of SMO/GLI inhibitors in clinical settings.
刺猬信号通路（Hh）-胶质瘤相关癌基因同源物（GLI）信号通路在哺乳动物中高度保守，在调节胚胎发育以及癌症的发生和进展中发挥着关键作用。GLI转录因子（GLI1、GLI2和GLI3）是Hh信号通路的效应器，通过依赖于平滑受体（SMO）和不依赖于SMO的机制进行调控。依赖于SMO的途径涉及常见的Hh-PTCH-SMO轴，这些水平的突变或转录及表观遗传失调会导致GLI转录因子的组成性激活。相反，不依赖于SMO的途径涉及外部信号通路及其相互作用蛋白对GLI转录因子的SMO旁路调节，或通过对GLI转录因子表达的表观遗传和转录调节。当失调时，GLI激活的这两种途径都与许多已知癌症的肿瘤发生密切相关，使其成为癌症治疗的重要靶点。因此，本综述描述了在多种癌症的肿瘤发生中GLI调节的各种依赖于SMO和不依赖于SMO的途径，以便全面了解涉及GLI调节的刺猬信号网络范式。深入了解GLI与各种信号元件之间的复杂相互作用，可能有助于在未来为治疗依赖于Hh-GLI的癌症带来新的治疗突破。最后，我们总结了关于Hh抑制剂在临床开发研究中的最新发现，并讨论了在临床环境中使用SMO/GLI抑制剂的挑战、前景和可能的方向。
