Feedback Circuit among INK4 Tumor Suppressors Constrains Human Glioblastoma Development

Abstract

We have developed a nonheuristic genome topography scan (GTS) algorithm to characterize the patterns of genomic alterations in human glioblastoma (GBM), identifying frequent p18(INK4C) and p16(INK4A) codeletion. Functional reconstitution of p18(INK4C) in GBM cells null for both p16(INK4A) and p18(INK4C) resulted in impaired cell-cycle progression and tumorigenic potential. Conversely, RNAi-mediated depletion of p18(INK4C) in p16(INK4A)-deficient primary astrocytes or established GBM cells enhanced tumorigenicity in vitro and in vivo. Furthermore, acute suppression of p16(INK4A) in primary astrocytes induced a concomitant increase in p18(INK4C). Together, these findings uncover a feedback regulatory circuit in the astrocytic lineage and demonstrate a bona fide tumor suppressor role for p18(INK4C) in human GBM wherein it functions cooperatively with other INK4 family members to constrain inappropriate proliferation.

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Affiliated Institutions

• Brigham and Women's Hospital US
• Dana-Farber Cancer Institute US
• Ludwig Cancer Research US
• Harvard University US
• Wellcome Sanger Institute GB
• Cornell University US
• Broad Institute US
• University of Cambridge GB
• Memorial Sloan Kettering Cancer Center US
• Institute of Cancer Research GB
• University of California, San Diego US

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