Hedgehog signaling drives medulloblastoma growth via CDK6
David R. Raleigh, … , Nicole Santos, Jeremy F. Reiter
David R. Raleigh, … , Nicole Santos, Jeremy F. Reiter
Published January 2, 2018
Citation Information: J Clin Invest. 2018;128(1):120-124. https://doi.org/10.1172/JCI92710.
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Categories: Concise Communication Oncology Therapeutics

Hedgehog signaling drives medulloblastoma growth via CDK6

Abstract

Medulloblastoma, an aggressive cancer of the cerebellum, is among the most common pediatric brain tumors. Approximately one-third of medulloblastomas are associated with misactivation of the Hedgehog (Hh) pathway. GLI family zinc finger 2 (GLI2) coordinates the Hh transcriptional program; however, the GLI2 targets that promote cancer cell proliferation are unknown. Here, we incorporated a Gli2-EGFP allele into 2 different genetic mouse models of Hh-associated medulloblastoma. Hh signaling induced GLI2 binding to the Cdk6 promoter and activated Cdk6 expression, thereby promoting uncontrolled cell proliferation. Genetic or pharmacological inhibition of CDK6 in mice repressed the growth of Hh-associated medulloblastoma and prolonged survival through inhibition of cell proliferation. In human medulloblastoma, misactivation of Hh signaling was associated with high levels of CDK6, pointing to CDK6 as a direct transcriptional target of the Hh pathway. These results suggest that CDK6 antagonists may be a promising therapeutic approach for Hh-associated medulloblastoma in humans.

Authors

David R. Raleigh, Pervinder K. Choksi, Alexis Leigh Krup, Wasima Mayer, Nicole Santos, Jeremy F. Reiter

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Figure 1

Hh signaling induces CDK6 in medulloblastoma.

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Hh signaling induces CDK6 in medulloblastoma. (A) Volcano plot generated...
(A) Volcano plot generated by RNA sequencing of the medulloblastomas from 3 P35 Math1-Cre SmoM2c Gli2-EGFP female mice relative to the cerebella of 3 P35 SmoM2c Gli2-EGFP female littermate controls. 2676 genes are differentially expressed with fold-change of 3 or more, P value of less than 0.008, and false discovery rate of 0.05 or less. Hh pathway targets and Cdk6 (red) are enriched in Hh-associated medulloblastoma. (B) Quantitative reverse-transcriptase PCR (qRT-PCR) demonstrates enrichment of Gli1 and enrichment of Cdk6 expression in Hh-associated medulloblastoma (blue) relative to age- and sex-matched littermate cerebella (gray). *P < 0.004, t test. n = 4 mice per genotype, representative of 3 experiments. (C) Immunoblot demonstrates elevated levels of CDK6, cyclin D1, and phospho-RB proteins in Hh-associated medulloblastoma. n = 2 mice, representative of 3 experiments. (D) qRT-PCR of ciliated NIH/3T3 cells treated either with SAG alone to activate the Hh pathway (green) or in conjunction with HLM006474 to inhibit E2F DNA binding (black). E2F antagonism inhibits induction of all cell cycle effectors in response to Hh stimulation except for Cdk6 and Ccnd1. *P < 0.05, t test. n = 3, representative of 3 experiments.