Dominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis

Human chromosome 9p21.3 is susceptible to inactivation in cell immortalization and diseases, such as cancer, coronary artery disease and type-2 diabetes. Although this locus encodes three cyclin-dependent kinase (CDK) inhibitors (p15(INK4B), p14(ARF) and p16(INK4A)), our understanding of their functions and modes of action is limited to the latter two. Here, we show that in vitro p15(INK4B) is markedly stronger than p16(INK4A) in inhibiting pRb1 phosphorylation, E2F activity and cell-cycle progression. In mice, urothelial cells expressing oncogenic HRas and lacking p15(INK4B), but not those expressing HRas and lacking p16(INK4A), develop early-onset bladder tumors. The potency of CDKN2B/p15(INK4B) in tumor suppression relies on its strong binding via key N-terminal residues to and inhibition of CDK4/CDK6. p15(INK4B) also binds and inhibits enolase-1, a glycolytic enzyme upregulated in most cancer types. Our results highlight the dual inhibition of p15(INK4B) on cell proliferation, and unveil mechanisms whereby p15(INK4B) aberrations may underpin cancer and non-cancer conditions.