@article{fb2c639a45bb41d5ab744510be9dca4e,
title = "Cilia-Associated Oxysterols Activate Smoothened",
abstract = "Primary cilia are required for Smoothened to transduce vertebrate Hedgehog signals, but how Smoothened accumulates in cilia and is activated is incompletely understood. Here, we identify cilia-associated oxysterols that promote Smoothened accumulation in cilia and activate the Hedgehog pathway. Our data reveal that cilia-associated oxysterols bind to two distinct Smoothened domains to modulate Smoothened accumulation in cilia and tune the intensity of Hedgehog pathway activation. We find that the oxysterol synthase HSD11β2 participates in the production of Smoothened-activating oxysterols and promotes Hedgehog pathway activity. Inhibiting oxysterol biosynthesis impedes oncogenic Hedgehog pathway activation and attenuates the growth of Hedgehog pathway-associated medulloblastoma, suggesting that targeted inhibition of Smoothened-activating oxysterol production may be therapeutically useful for patients with Hedgehog-associated cancers. How Smoothened localizes to primary cilia and is activated is poorly understood. Raleigh et al. find that cilia contain oxysterol lipids that bind to Smoothened and activate the Hedgehog pathway. Moreover, they identify an enzyme involved in cilia-associated oxysterol biosynthesis that is enriched in Hedgehog pathway-associated medulloblastoma and that blocking this enzyme using a compound in black licorice inhibits tumor growth.",
keywords = "CBP, HSD11β2, Hedgehog, Smoothened, cilia, lipid, medulloblastoma, oxysterol, primary cilium, sterol",
author = "Raleigh, {David R.} and Navdar Sever and Choksi, {Pervinder K.} and Sigg, {Monika Abedin} and Hines, {Kelly M.} and Thompson, {Bonne M.} and Daniel Elnatan and Priyadarshini Jaishankar and Paola Bisignano and Garcia-Gonzalo, {Francesc R.} and Krup, {Alexis Leigh} and Markus Eberl and Byrne, {Eamon F.X.} and Christian Siebold and Wong, {Sunny Y.} and Renslo, {Adam R.} and Michael Grabe and McDonald, {Jeffrey G.} and Libin Xu and Beachy, {Philip A.} and Reiter, {Jeremy F.}",
note = "Funding Information: We thank Dr. Ming-Zhi Zhang for providing the Hsd11β2c mouse allele, Dr. Ljiljana Milenkovic for providing Med1 cells, Dr. Rune Toftg{\aa}rd for providing Sufu−/− MEFs, Kaitlyn Eckert for developing the modified oxysterol extraction method used for mass spectrometry analyses done at the University of Texas Southwestern Medical Center, and Dr. Lindsay Raleigh for providing natural sea water for sea urchin embryo culture. This work was supported by grants from the NIH (HL007731 and CA212279-01), the UCSF Physician Scientist Scholar Program, the American Society of Clinical Oncology, the Rally Foundation for Childhood Cancer Research, and the American Brain Tumor Association to D.R.R.; the NIH program Project Grant to Molecular Genetics (HL20948) to J.G.M.; Cancer Research UK (C20724 and A14414) and the European Research Council (647278) to C.S.; the NIH (AR065409 and HD092659) to S.Y.W. and L.X., respectively; the NIH (R01GM102498), the Ludwig Cancer Institute, and the Howard Hughes Medical Institute to P.A.B.; and the NIH (AR054396 and GM095941), the Burroughs Wellcome Fund, and the Packard Foundation to J.F.R. Funding Information: We thank Dr. Ming-Zhi Zhang for providing the Hsd11β2 c mouse allele, Dr. Ljiljana Milenkovic for providing Med1 cells, Dr. Rune Toftg{\aa}rd for providing Sufu −/− MEFs, Kaitlyn Eckert for developing the modified oxysterol extraction method used for mass spectrometry analyses done at the University of Texas Southwestern Medical Center, and Dr. Lindsay Raleigh for providing natural sea water for sea urchin embryo culture. This work was supported by grants from the NIH ( HL007731 and CA212279-01 ), the UCSF Physician Scientist Scholar Program , the American Society of Clinical Oncology , the Rally Foundation for Childhood Cancer Research , and the American Brain Tumor Association to D.R.R.; the NIH program Project Grant to Molecular Genetics ( HL20948 ) to J.G.M.; Cancer Research UK ( C20724 and A14414 ) and the European Research Council ( 647278 ) to C.S.; the NIH ( AR065409 and HD092659 ) to S.Y.W. and L.X., respectively; the NIH ( R01GM102498 ), the Ludwig Cancer Institute , and the Howard Hughes Medical Institute to P.A.B.; and the NIH ( AR054396 and GM095941 ), the Burroughs Wellcome Fund , and the Packard Foundation to J.F.R. Publisher Copyright: {\textcopyright} 2018",
year = "2018",
month = oct,
day = "18",
doi = "10.1016/j.molcel.2018.08.034",
language = "English (US)",
volume = "72",
pages = "316--327.e5",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "2",
}