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 p18INK4C 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.