1] Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
1] Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada [2] Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada [3] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Oncogene. 2014 May 15;33(20):2674-80. doi: 10.1038/onc.2013.212. Epub 2013 Jun 10.
Basal cell carcinoma (BCC), the most common type of cancer, is characterized by aberrant Hedgehog (Hh) pathway activity. Mutations in pathway components, such as PATCHED1 (PTCH1), are commonly found in BCC. While the tumor suppressor role of PTCH1 in BCC is well established, how Hh pathway activation disrupts normal skin homeostasis to promote BCC formationremains poorly understood. Like Ptc1, Sufu is a major negative regulator of the Hh pathway. Previously, we showed that inactivation of Sufu in the skin does not result in BCC formation. Why loss of Ptc1, but not Sufu, in the epidermis induces BCC formation is unclear. In this report, we utilized gene expression profiling to identify biological pathways and processes that distinguish Sufu from Ptc1 mutants, and discovered a novel role for Sufu in cell cycle regulation. We demonstrated that the Hh pathway activation inSufu and Ptc1 mutant skin is associated with abnormal cell cycle entry, ectopic expression of D-type cyclins and increasedDNA damage. However, despite the presence of DNA damage, p53 stabilization was impaired in the mutant skin. Alternative mechanism to halt genomic instability is the activation of G2/M cell cycle checkpoint, which can occur independent of p53. We found that while Ptc1 mutant cells continue to cycle, which would favor genomic instability, loss of Sufu results in G2/M cell cycle arrest.This finding may explain why inactivation of Sufu is not sufficient to drive BCC formation. Taken together, these studies revealed a unique role for Sufu in G2/M phase progression, and uncovered the molecular and cellular features associated with Hh-driven BCC.
基底细胞癌（BCC）是最常见的癌症类型，其特征是 Hedgehog（Hh）信号通路活性异常。通路成分（如 PATCHED1，PTCH1）的突变在 BCC 中很常见。虽然 PTCH1 在 BCC 中的肿瘤抑制作用已得到充分证实，但 Hh 信号通路的激活如何破坏正常皮肤的动态平衡以促进 BCC 的形成仍知之甚少。与 Ptc1 一样，Sufu 是 Hh 信号通路的主要负调控因子。之前，我们发现皮肤中 Sufu 的失活不会导致 BCC 的形成。为什么表皮中 Ptc1 的缺失而不是 Sufu 的缺失会诱导 BCC 的形成尚不清楚。在本报告中，我们利用基因表达谱分析来鉴定区分 Sufu 和 Ptc1 突变体的生物学途径和过程，并发现了 Sufu 在细胞周期调控中的新作用。我们证明了 Sufu 和 Ptc1 突变体皮肤中的 Hh 信号通路激活与异常细胞周期进入、D 型细胞周期蛋白的异位表达和增加的 DNA 损伤有关。然而，尽管存在 DNA 损伤，突变体皮肤中的 p53 稳定化受到损害。阻止基因组不稳定性的替代机制是激活 G2/M 细胞周期检查点，该检查点可以独立于 p53 发生。我们发现，虽然 Ptc1 突变细胞继续循环，这有利于基因组不稳定性，但 Sufu 的缺失会导致 G2/M 细胞周期停滞。这一发现可能解释了为什么 Sufu 的失活不足以驱动 BCC 的形成。总之，这些研究揭示了 Sufu 在 G2/M 期进展中的独特作用，并揭示了与 Hh 驱动的 BCC 相关的分子和细胞特征。
