By identifying and validating the PROX1 binding site in the SIRT3 promoter, we confirmed that PROX1 is the transcription factor responsible for decreased SIRT3 expression in colon cancer cells; moreover, knocking down PROX1 expression increased SIRT3 expression and reversed the malignant properties of CRC. Here, PROX1 is linked to malignant colon neoplasm.