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.