RT Journal Article SR Electronic T1 mTORC1-mediated inhibition of 4EBP1 is essential for Hedgehog (HH) signaling and can be targeted to suppress HH-driven medulloblastoma JF bioRxiv FD Cold Spring Harbor Laboratory SP 130872 DO 10.1101/130872 A1 Chang-Chih Wu A1 Shirui Hou A1 Brent A. Orr A1 Yong Ha Youn A1 Fanny Roth A1 Charles G. Eberhart A1 Young-Goo Han YR 2017 UL http://biorxiv.org/content/early/2017/04/25/130872.abstract AB Mechanistic target of rapamycin (MTOR) cooperates with Hedgehog (HH) signaling, but the underlying mechanisms are incompletely understood. Here, we provide genetic, biochemical, and pharmacologic evidence that MTOR complex 1 (mTORC1)-dependent translation is a prerequisite for HH signaling. The genetic loss of mTORC1 function inhibited HH signaling– driven growth of the cerebellum and medulloblastoma. Inhibiting translation or mTORC1 blocked HH signaling. Depleting 4EBP1, an mTORC1 target that inhibits translation, alleviated the dependence of HH signaling on mTORC1. Consistent with this, phosphorylated 4EBP1 levels were elevated in HH signaling–driven medulloblastomas in mice and humans. In mice, an mTORC1 inhibitor suppressed medulloblastoma driven by a mutant SMO that is resistant to an SMO inhibitor in the clinic, prolonging the survival of the mice. Our study reveals mTORC1-mediated translation to be a key component of HH signaling and an important target for treating medulloblastoma and other cancers driven by HH signaling.