Critically, knockdown of <i>S100A14</i> abrogated the pro-metastatic phenotype of cancer cells.<h4>Conclusion</h4>This study identifies <i>S100A14</i> promotes PC progression by stabilizing <i>S100A16</i> and suppressing the tumor-suppressive <i>p53/p21</i> pathway; knockdown of <i>S100A14</i> can reverse the above effects, restore <i>p53</i> function, and enhance cancer cell apoptosis. Here, S100A16 is linked to cancer.