Recently, the team led by Professor Zhu Yushan from Nankai University College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, and Interdisciplinary Science Center for Cell Response, published the research findings entitled "Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression" on the journal eLife online. The study found that hypoxic stress can affect the molecular mechanism of tumor progression by regulating the ubiquitination modification and degradation of key tumor regulator DBC1 (Deleted in Breast Cancer 1) protein, revealing the molecular mechanism of the hypoxic microenvironment that regulates the tumor cell response from a new perspective.
In this program, the research team first compared and analyzed the RNA-seq of breast cancer cells under normal oxygen and hypoxic conditions, and found that the signal channel activity positively regulated by DBC1 under hypoxic stress conditions was significantly reduced. At the same time, a biochemical test study confirmed that hypoxic stress can induce DBC1 to undergo ubiquitination modification and participate in the regulation of downstream signal channels through the degradation of proteasome pathway. Through mass spectrometry and biochemical test verification, E3 ubiquitin ligase SIAH2 and deubiquitinating enzyme OTUD5 that regulate DBC1 ubiquitination modification were screened out and identified. A molecular mechanism study found that hypoxic stress induces a weakening interaction between OTUD5 and DBC1, while SIAH2 has competitive binding with DBC1 and catalyzes its 287 lysine residues to undergo ubiquitination modification and degradation of the proteasome pathway. Finally, it was confirmed through clinical tissue samples that SIAH2 and DBC1 protein levels were negatively correlated in breast cancer patients, and the protein levels of DBC1 were significantly correlated with the clinical stages and pathological grading of cancer patients.
The study has enriched the dynamic regulation mechanism of hypoxic microenvironment by affecting the ubiquitination modification and protein stability of key protein factors in tumor cells, thus affecting the occurrence and progression of tumors; clarified the important role of the protein stability of the key tumor regulator DBC1 in tumor cell's resistance to adverse environment as well as the occurrence and development of breast cancer; and provided new targets and strategies for the prevention and treatment of breast cancer.
Liu Qiangqiang, a doctoral student at NKU College of Life Sciences, is the first author of this paper, and Professor Zhu Yushan of Nankai University is the corresponding author. The team led by Professor Hu Gang from NKU School of Statistics and Data Science provided technical support for data analysis through RNAseq.
Link to the paper: https://elifesciences.org/articles/8124
