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Mechanistic understanding of hypoxia-responsive signaling pathways provides important insights into oxygen- and metabolism-dependent cellular phenotypes in diseases. Using SILAC-based quantitative proteomics, we provided a quantitative map identifying over 6300 protein groups in response to hypoxia in prostate cancer cells and identified both canonical and novel cellular networks dynamically regulated under hypoxia. Particularly, we identified SDE2, a DNA stress response modulator, that was significantly downregulated by hypoxia, independent of HIF (hypoxia-inducible factor) transcriptional activity. Mechanistically, hypoxia treatment promoted SDE2 polyubiquitination and degradation. Such regulation is independent of previously identified Arg/N-end rule proteolysis or the ubiquitin E3 ligase, CDT2. Depletion of SDE2 increased cellular sensitivity to DNA damage and inhibited cell proliferation. Interestingly, either SDE2 depletion or hypoxia treatment potentiated DNA damage-induced PCNA (proliferating cell nuclear antigen) monoubiquitination, a key step for translesion DNA synthesis. Furthermore, knockdown of SDE2 desensitized, while overexpression of SDE2 protected the hypoxia-mediated regulation of PCNA monoubiquitination upon DNA damage. Taken together, our quantitative proteomics and biochemical study revealed diverse hypoxia-responsive pathways that strongly associated with prostate cancer tumorigenesis and identified the functional roles of SDE2 and hypoxia in regulating DNA damage-induced PCNA monoubiquitination, suggesting a possible link between hypoxic microenvironment and the activation of error-prone DNA repair pathway in tumor cells.

Proteome dynamics analysis identifies functional roles of SDE2 and hypoxia in DNA damage response in prostate cancer cells