In summary, from a novel point of view, our findings provided strong evidence for the suppressive effect of p27 in the process of HIF-1α protein synthesis in arsenite responses by regulating the PHLPP-Ras-ERK-p90RSK-S6 axis, which may help to upgrade our understanding about the tumor-suppressive functions of p27. Here, RPS6KA1 is linked to neoplasm.