Feedback Circuit among INK4 Tumor Suppressors Constrains Human Glioblastoma Development

<h2>Summary</h2> We have developed a nonheuristic genome topography scan (GTS) algorithm to characterize the patterns of genomic alterations in human glioblastoma (GBM), identifying frequent <i>p18^INK4C</i> and <i>p16^INK4A</i> codeletion. Functional reconstitution of p18^INK4C in GBM cells null for both <i>p16^INK4A</i> and <i>p18^INK4C</i> resulted in impaired cell-cycle progression and tumorigenic potential. Conversely, RNAi-mediated depletion of <i>p18^INK4C</i> in <i>p16^INK4A</i>-deficient primary astrocytes or established GBM cells enhanced tumorigenicity in vitro and in vivo. Furthermore, acute suppression of <i>p16^INK4A</i> in primary astrocytes induced a concomitant increase in <i>p18^INK4C</i>. 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.