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. 2021 May 17;19:56. doi: 10.1186/s12964-021-00737-8

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© The Author(s) 2021

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 1 — Group B KCTDs (KCASH family) suppress Hh/Gli1-dependent tumorigenesis. An example of cooperation between KCTD members. The Hh pathway is activated in the presence of SHh ligand, which binding to PTCH abolishes PTCH-mediated SMO inhibition allowing SMO to translocate into the primary cilium. Subsequently, ciliary trafficking of Hh pathway components leads to activation and transport of the transcription factor Gli1 towards the nucleus, where it transcribes target genes involved in proliferation and tumorigenesis. Along the way, Gli1 is kept transcriptionally active by HDAC1 deacetylation. The three members of the KCASH family act as negative regulators, promoting the ubiquitination and proteasomal degradation of HDAC1, thereby inhibiting transcriptional activity of Gli1. In this context, another KCTD protein, KCTD15, positively regulates KCASH2^KCTD21 protein levels, enhancing its inhibitory activity. SHh: Sonic Hedgehog. PTCH: Patched