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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-08, Vol.104 (32), p.13040-13045
• Main Authors: Wei, Guangwei, Ku, Stephen, Ma, Gene K, Saito, Shin'ichi, Tang, Amy A, Zhang, Jiasheng, Mao, Jian-Hua, Appella, Ettore, Balmain, Allan, Huang, Eric J
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - physiology; Biological Sciences; Carrier Proteins - physiology; Cell cycle; Cell growth; Cell lines; Cell Proliferation; Cells, Cultured; Co repressor proteins; Cyclin D1 - genetics; Cyclins; Epidermis - cytology; Keratinocytes; Keratinocytes - pathology; Lymphoid Enhancer-Binding Factor 1 - physiology; Mice; Protein-Serine-Threonine Kinases - physiology; Repressor Proteins - physiology; Skin; Skin cancers; Skin Neoplasms - prevention & control; Stem cells; Stem Cells - cytology; Transcriptional Activation; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0703213104

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.