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COOH-Terminal Binding Protein Regulates Expression of the p16^INK4A Tumor Suppressor and Senescence in Primary Human Cells

¹ Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center and Harvard Medical School and ² Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts

Requests for reprints: James W. Rocco, Massachusetts General Hospital Cancer Center, Jackson 904, 55 Fruit Street, Boston, MA 02114. Phone: 617-726-5251; Fax: 617-726-8623; E-mail: jrocco{at}partners.org.

Key Words: CtBP • p16 • hypoxia • senescence • culture stress

The p16/pocket-protein pathway sets a balance between tumor suppression and capacity for tissue regeneration. Understanding the upstream signaling pathway that turns on the expression of p16 is required both for knowing the tumorigenic stresses from which this pathway provides protection and for appreciating the selective pressure that leads to the loss of this pathway in most human tumors. We report that COOH-terminal binding protein (CtBP), a physiologically regulated transcriptional corepressor that dimerizes to hold together repressive complexes, regulates p16 expression in primary human fibroblasts and keratinocytes. Interfering with CtBP-mediated repression increased p16 expression and accelerated senescence. CtBP had little influence on the expression of the alternate product of the CDKN2A tumor-suppressor gene, p14^ARF. Loss of CtBP-mediated repression diminished the Polycomb-based epigenetic histone mark that is reported to favor silencing of p16 via DNA methylation. Enhancing CtBP-mediated repression by growing cells in low oxygen increased the association of CtBP with the p16 promoter, as assessed by chromatin immunoprecipitation, and reduced p16 expression. Stresses and stimuli that reduce CtBP-mediated repression are associated with increased p16 expression; therefore, CtBP may provide a common final target for regulating the balance among tumor suppression, regenerative capacity, and senescence. [Cancer Res 2008;68(15):6049–53]

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