Abstract 4544: FBW7 induces S-phase arrest caused by DNA double strand breaks through targeting SOX9 for proteasomal degradation

Abstract

SOX9 encodes a transcription factor that governs cell fate specification throughout development and tissue homeostasis. Elevated SOX9 is implicated in the genesis or progression of many human tumors through increasing cell proliferation and epithelial-mesenchymal transition. We observed that, in response to UV irradiation or certain chemotherapeutic agents, SOX9 is actively and rapidly degraded by a ubiquitin pathway dependent mechanism across several different tumor types including lung cancer, colon cancer, osteosarcoma and melanoma, as well as normal human bronchial epithelial cells. We found that SOX9 is phosphorylated by GSK3β at Ser-236, facilitating the direct binding and degradation of SOX9 via the F box protein, FBW7α. We also determined that the de-ubiquitinase, USP28, stabilizes SOX9 under normal conditions by sequestering FBW7, but is released from FBW7 after UV irradiation, allowing FBW7 to bind SOX9 and target it for destruction. DNA damage-induced SOX9 degradation was independent of p53, ATM, ATR and MAPK pathways. Failure to deplete SOX9 attenuated the DNA damage-induced intra-S-phase checkpoint and increased long-term cell survival. Moreover, mutations within the FBW7 phosphodegron binding site of SOX9 prevented SOX9 degradation after DNA damage, and incurred resistance of non-small cell lung cancer (NSCLC) cells to cisplatin in vivo. We found that cancer patients with tumors expressing high Sox9 and low Fbw7 levels exhibit inferior survival. Our discovery reveals a novel function of SOX9 in the cellular response to DNA damage. Induced degradation of SOX9 may be part of the protection mechanisms to maintain genomic stability. This new regulatory mechanism of the FBW7-SOX9 axis in cancer could have diagnostic and therapeutic implications. Citation Format: Xuehui Hong, Wenyu Liu, Ruipeng Song, Hiroyuki Inuzuka, Hatem E. Sabaawy, Katherine M. Morgan, Jamie J. Shah, Samuel F. Bunting, Xing Feng, Chi-Kwan Tsang, Zhiyuan Shen, X. F. Steven Zheng, LianXin Liu, Sharon R. Pine. FBW7 induces S-phase arrest caused by DNA double strand breaks through targeting SOX9 for proteasomal degradation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4544.