ALDH2 promotes cancer stemness and metastasis in colorectal cancer through activating β‐catenin signaling

Abstract Colorectal cancer (CRC) is the primary cause of death from gastrointestinal cancers. Aldehyde dehydrogenase 2 (ALDH2), a crucial mitochondrial enzyme for the oxidative pathway of alcohol metabolism, plays a dual role in cancer progression. In some cancers, it is tumor suppressive; in others, it drives cancer progression. However, whether targeting ALDH2 has any therapeutic implications or prognostic value in CRC is still unclear. Here, we investigated the role of ALDH2 in CRC progression by targeting its enzymatic activity rather than gene expression. We found that inhibiting ALDH2 by CVT‐10216 and daidzein significantly decrease migration and stemness properties of both DLD‐1 and HCT 116 cells, whereas activating ALDH2 by Alda‐1 enhances migration rate. Concomitantly, ALDH2 inhibition by both CVT‐10216 and daidzein downregulates the mRNA levels of fibronectin, snail, twist, MMP7, CD44, c‐Myc, SOX2, and OCT‐4, which are oncogenic in the advanced stage of CRC. Furthermore, Gene Set Enrichment Analysis (GSEA) on ALDH2 co‐expressed genes from The Cancer Genome Atlas (TCGA) revealed that MYC target gene sets are upregulated. We found that ALDH2 inhibition decreased the nuclear protein levels of pGSK3β serine 9 and c‐Myc. This suggests that ALDH2 probably targets β‐catenin signaling in CRC cells. Together, our results demonstrate the prognostic value of ALDH2 in CRC as it regulates both CRC stemness and migration. Our findings also propose that the plant‐derived isoflavone daidzein could be a potential chemotherapeutic drug targeting ALDH2 in CRC.