HIPK2 represses β-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis

Transcriptional control by β-catenin and lymphoid enhancer-binding factor 1 (LEF1)/T cell factor regulates proliferation in stem cells and tumorigenesis. Here we provide evidence that transcriptional co repressor homeodomain interacting protein kinase 2 (HIPK2) controls the number of stem and progenitor cells in the skin and the susceptibility to develop squamous cell carcinoma. Loss of HIPK2 leads to increased proliferative potential, more rapid G1–S transition in cell cycle, and expansion of the epidermal stem cell compartment. Among the critical regulators of G1–S transition in the cell cycle, only cyclin D1 is selectively up-regulated in cells lacking HIPK2. Conversely, overexpression of HIPK2 suppresses LEF1/β-catenin-mediated transcriptional activation of cyclin D1 expression. However, deletion of the C-terminal YH domain of HIPK2 completely abolishes its ability to recruit another transcriptional corepressor CtBP and suppress LEF1/β-catenin-mediated transcription. To determine whether loss of HIPK2 leads to increased susceptibility to tumorigenesis, we treat wild-type, Hipk2+/−, andHipk2−/− mice with the two-stage carcinogenesis protocol. Our results indicate that more skin tumors are induced in Hipk2+/− and Hipk2−/− mutants, with most of the tumors showing shortened incubation time and malignant progression. Together, our results indicate that HIPK2 is a tumor suppressor that controls proliferation by antagonizing LEF1/β-catenin-mediated transcription. Loss of HIPK2 synergizes with activation of H-ras to induce tumorigenesis.

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