Hypoxia is a common feature of solid
tumors and represents a critical factor in their progression and responsiveness to
chemotherapy and
radiotherapy. We now report that hypoxic exposure of
colon cancer cells decreased the
protein levels of the cell cycle-controlling
phosphatase Cdc25A.
Hypoxia decreased the mitotic population and caused S-phase arrest in these cells. Suppression of Cdc25A was
phosphatase family member-specific, as a similar decrease was not observed with closely related Cdc25B or Cdc25C
phosphatases. Pharmacological and genetic blockade of Chk1 and Chk2 failed to inhibit the
hypoxia-mediated loss of Cdc25A, indicating this process was not regulated by a traditional ATM/ATR checkpoint response. In addition,
hypoxia did not affect ectopically expressed Cdc25A levels suggesting independence from an increase in proteasomal degradation. Cdc25A
mRNA levels also decreased in human
colon cancer cells 24 hr after
hypoxia supporting a mechanistic role for decreased Cdc25A expression or mRNA stability. The reduction in Cdc25A
mRNA and
protein was dependent on the
cyclin-dependent kinase inhibitor p21 and miR-21, which were upregulated in HCT116
colon cancer cells during
hypoxia. These results reveal previously unknown mechanisms for the transient suppression of Cdc25A, providing a coordinated and fundamental adaptive change that may be exploited by
cancer cells conferring proliferative and survival advantages.