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    • br Regulation of the GLI

    2022-01-17


    Regulation of the GLI code by non-HH signals and by the oncogenic load The GLI code may be seen as the essential parameter to regulate canonical HH output. Its regulation first appeared to be strictly dependent on the presence of specific levels of HH ligands. Indeed, GLI1 transcription is so far the only general biomarker of a cell's response to HH ligands [12], it can be a diagnostic tool for HH pathway activity [52] and is used to measure the efficiency of SMOH blockers in clinical samples [61], [62], [63]. However, surprising data revealed that the GLI1 code and activity can also be modulated by non-HH signals [64], [65]. Such regulation occurs in normal and in disease contexts and here we highlight key examples (Fig. 2).
    Mechanisms of GLI regulation
    Outlook Whereas great progress has been made to understand how the GLI proteins act (e.g., reviewed in [7], [21], [58], [59], [64], [163]), much remains to be understood. For example, it is not clear what are effective endogenous concentrations of GLI proteins, how they interact with co-factors, how can they be modified in jnk inhibitor receiving simultaneous inputs, how their activity can be affected by and affect epigenetic changes, how they are protected from cleavage or modification, or even how the pathway is effectively turned off when required. A more anthropocentric goal is to understand how the GLI code is perverted in human disease, and specifically in cancer, through pathway corruption and the oncogenic load. Such knowledge will possibly lead us to design novel and more efficient therapies against multiple forms of deadly cancers, including those of the brain, intestine, lung, skin, pancreas and other organs. Indeed, the involvement of HH-GLI signaling in normal stem cell lineages and in cancer stem cells [54] raises the possibility that novel molecular approaches to block positive GLI function, reverting the GLI code, could be highly beneficial. For example, the discovery of aPKC, PI3K/AKT, mTOR/S6K or EGF signaling (see above) as part of the oncogenic load and, importantly, as druggable GLI modulators has already pointed out possible ways of how to design novel combination treatments with improved therapeutic benefit [64], [65], [90], [98], [164], [165]. However, despite the increasing number of studies of GLI regulation in health and disease, we are only beginning to realize the remarkable complexity of context-dependent regulatory processes affecting the GLI code. The identification and in depth analysis of modifiers of the GLI code will guide us to the development of better rational combination treatments by synergistically targeting the core of the HH-GLI pathway itself, and its modifiers. This will also open therapeutic opportunities to tackle the problem of relapse and drug resistance, as exemplified by the successful targeting of aPKC in SMOH inhibitor-resistant basal cell carcinomas [156]. We are now entering an era where the GLI transcription factors and their modulators are beginning to take center stage as drug targets. Targeting transcription factors for cancer therapy has long been considered not effective, but clearly the number of recent examples such as those mentioned above along with the identification of small molecule GLI antagonists [166], [167] provide ample proof-of-concept for the therapeutic relevance of such an approach. Given the essential function of GLIs in normal and malignant stem cells, the systematic identification and functional analysis of GLI modulators, particularly of those amenable to small molecule targeting, as well as studies addressing their context-dependent activity will be an area of intense future research with significant impact on several medical areas such as cancer, tissue regeneration and wound healing.
    Acknowledgements
    Work of the Aberger lab was supported by the Austrian Science Fund FWF (Projects P16518, P20652 and P25629), the Austrian Genome Program Gen-AU/Med-Sys (Project MoGLI), the European FP7 Marie-Curie Initial Training Network HEALING and the priority program Biosciences and Health of the Paris-Lodron University of Salzburg.