Year: 2017
Type: article
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.
DOI: 10.1172/jci92710
Institution: University of California, San Francisco
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: David and Lucile Packard Foundation, Burroughs Wellcome Fund, V Foundation for Cancer Research, American Brain Tumor Association, Rally Foundation, American Society of Clinical Oncology, National Institutes of Health, University of California, San Francisco, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH Clinical Center
OpenAlex ID: W2769472506