A Novel Mechanism for Activation of GLI1 by Nuclear SMO That Escapes Anti-SMO Inhibitors

Cancer Research
Muhammad M RahmanGraham W Neill

Abstract

Small-molecule inhibitors of the Hedgehog (HH) pathway receptor Smoothened (SMO) have been effective in treating some patients with basal cell carcinoma (BCC), where the HH pathway is often activated, but many patients respond poorly. In this study, we report the results of investigations on PTCH1 signaling in the HH pathway that suggest why most patients with BCC respond poorly to SMO inhibitors. In immortalized human keratinocytes, PTCH1 silencing led to the generation of a compact, holoclone-like morphology with increased expression of SMO and the downstream HH pathway transcription factor GLI1. Notably, although siRNA silencing of SMO in PTCH1-silenced cells was sufficient to suppress GLI1 activity, this effect was not phenocopied by pharmacologic inhibition of SMO, suggesting the presence of a second undefined pathway through which SMO can induce GLI1. Consistent with this possibility, we observed increased nuclear localization of SMO in PTCH1-silenced cells as mediated by a putative SMO nuclear/nucleolar localization signal [N(o)LS]. Mutational inactivation of the N(o)LS ablated this increase and suppressed GLI1 induction. Immunohistologic analysis of human and mouse BCC confirmed evidence of nuclear SMO, although the pat...Continue Reading

References

Mar 1, 1988·The Journal of Pathology·M J Egan, J Crocker
Oct 1, 1994·The Journal of Investigative Dermatology·T V KarelinaA Z Eisen
Dec 14, 1999·The Journal of Laboratory and Clinical Medicine·M DezawaN Suzuki
Mar 4, 2000·Nature Genetics·M GrachtchoukA A Dlugosz
May 30, 2003·The EMBO Journal·Vladimir GrachtchoukAndrzej A Dlugosz
Feb 21, 2006·Cancer Research·Christelle AdolpheBrandon Wainwright
Jan 24, 2007·The Journal of Cell Biology·Shazia S ChaudhryCay M Kielty
Sep 25, 2008·Nature Reviews. Cancer·Ervin H Epstein
Feb 21, 2009·EMBO Reports·Edward Emmott, Julian A Hiscox
Feb 16, 2010·Nature Cell Biology·Khalil Kass YoussefCédric Blanpain
Mar 17, 2010·The American Journal of Pathology·Blanche Ka Ki LoKevin John McElwee
Jul 6, 2010·Nature Neuroscience·Timothy J Mosca, Thomas L Schwarz
Jan 11, 2011·Cancer Cell·Grace Ying WangErvin H Epstein
Apr 27, 2011·The Journal of Clinical Investigation·Marina GrachtchoukAndrzej A Dlugosz
Jan 24, 2012·The Journal of Biological Chemistry·Crystal Zoe HoeppnerRichard D Ye
Oct 18, 2012·Science Signaling·David J RobbinsNatalia A Riobo
Feb 15, 2013·The Journal of Investigative Dermatology·Michal R GdulaVladimir A Botchkarev
Jan 7, 2014·Biochimica Et Biophysica Acta·Jaclyn E QuinRoss D Hannan
Feb 20, 2014·FEBS Letters·Susana MoleirinhoJoseph L Kissil
Feb 28, 2014·The Journal of Pathology·Karwan A MoutasimGareth J Thomas
Apr 10, 2015·Nature Communications·Simon N StaceyKari Stefansson
May 16, 2015·Expert Opinion on Therapeutic Targets·Jean-Sébastien JoyalSylvain Chemtob
Aug 14, 2015·European Journal of Clinical Investigation·George FotopoulosGeorge Pentheroudakis
Oct 4, 2015·Trends in Pharmacological Sciences·Angela M ArensdorfStacey K Ogden
Mar 22, 2016·Colorectal Disease : the Official Journal of the Association of Coloproctology of Great Britain and Ireland·S L RasmussenO Thorlacius-Ussing
Oct 27, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Atul KumarBithiah Grace Jaganathan
Jul 14, 2016·Molecular Biology Reports·Anna GoździalskaMaciej Pastuszczak
Dec 9, 2016·Current Pharmaceutical Design·Vivian T Yin, Bita Esmaeli
Nov 21, 2017·Cell Death Discovery·Matteo CassandriGiuseppe Raschellà

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