Journal
MOLECULAR CELL
Volume 72, Issue 2, Pages 316-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2018.08.034
Keywords
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Funding
- NIH [HL007731, CA212279-01, AR065409, HD092659, AR054396, GM095941, R01GM102498]
- UCSF Physician Scientist Scholar Program
- American Society of Clinical Oncology
- Rally Foundation for Childhood Cancer Research
- American Brain Tumor Association
- NIH program Project [HL20948]
- Cancer Research UK [C20724, A14414]
- European Research Council [647278]
- Ludwig Cancer Institute
- Howard Hughes Medical Institute
- Burroughs Wellcome Fund
- Packard Foundation
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [R01HD092659] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [K08CA212279] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR054396, R01AR065409] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK098722] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM102498, R01GM089740, R01GM095941] Funding Source: NIH RePORTER
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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 HSD11 beta 2 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.
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