eLife (Aug 2022)
Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression
- Qiangqiang Liu,
- Qian Luo,
- Jianyu Feng,
- Yanping Zhao,
- Biao Ma,
- Hongcheng Cheng,
- Tian Zhao,
- Hong Lei,
- Chenglong Mu,
- Linbo Chen,
- Yuanyuan Meng,
- Jiaojiao Zhang,
- Yijia Long,
- Jingyi Su,
- Guo Chen,
- Yanjun Li,
- Gang Hu,
- Xudong Liao,
- Quan Chen,
- Yushan Zhu
Affiliations
- Qiangqiang Liu
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Qian Luo
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Jianyu Feng
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Yanping Zhao
- School of Statistics and Data Science, LPMC and KLMDASR, Nankai University, Tianjin, China
- Biao Ma
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Hongcheng Cheng
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Tian Zhao
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Hong Lei
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Chenglong Mu
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Linbo Chen
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Yuanyuan Meng
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Jiaojiao Zhang
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Yijia Long
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Jingyi Su
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Guo Chen
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Yanjun Li
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Gang Hu
- School of Statistics and Data Science, LPMC and KLMDASR, Nankai University, Tianjin, China
- Xudong Liao
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Quan Chen
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- Yushan Zhu
- ORCiD
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Haihe Laboratory of Cell Ecosystem, Nankai University, Tianjin, China
- DOI
- https://doi.org/10.7554/eLife.81247
- Journal volume & issue
-
Vol. 11
Abstract
DBC1 has been characterized as a key regulator of physiological and pathophysiological activities, such as DNA damage, senescence, and tumorigenesis. However, the mechanism by which the functional stability of DBC1 is regulated has yet to be elucidated. Here, we report that the ubiquitination-mediated degradation of DBC1 is regulated by the E3 ubiquitin ligase SIAH2 and deubiquitinase OTUD5 under hypoxic stress. Mechanistically, hypoxia promoted DBC1 to interact with SIAH2 but not OTUD5, resulting in the ubiquitination and subsequent degradation of DBC1 through the ubiquitin–proteasome pathway. SIAH2 knockout inhibited tumor cell proliferation and migration, which could be rescued by double knockout of SIAH2/CCAR2. Human tissue microarray analysis further revealed that the SIAH2/DBC1 axis was responsible for tumor progression under hypoxic stress. These findings define a key role of the hypoxia-mediated SIAH2-DBC1 pathway in the progression of human breast cancer and provide novel insights into the metastatic mechanism of breast cancer.
Keywords
