Downregulated ALDH2 Contributes to Tumor Progression and Targeted Therapy Resistance in Human Metastatic Melanoma Cells

Aldehyde dehydrogenase 2 (ALDH2) is a crucial detoxifying enzyme that eliminates toxic aldehydes. ALDH2 deficiency has been linked to various human diseases, including certain cancers. We have previously reported <i>ALDH2</i> downregulation in human melanoma tissues. Here, we further investigated the biological significance of <i>ALDH2</i> downregulation in this malignancy. Analysis of TCGA dataset revealed that low <i>ALDH2</i> expression correlates with poorer survival in metastatic melanoma. Examination of human metastatic melanoma cell lines confirmed that most had <i>ALDH2</i> downregulation (<i>ALDH2</i>-low) compared to primary melanocytes. In contrast, a small subset of metastatic melanoma cell lines exhibited normal <i>ALDH2</i> levels (<i>ALDH2</i>-normal). CRISPR/Cas9-mediated <i>ALDH2</i> knockout in <i>ALDH2</i>-normal A375 cells promoted tumor growth and MAPK/ERK activation. Given the pivotal role of MAPK/ERK signaling in melanoma and cellular response to acetaldehyde, we compared A375 with <i>ALDH2</i>-low SK-MEL-28 and 1205Lu cells. <i>ALDH2</i>-low cells were intrinsically resistant to BRAF and MEK inhibitors, whereas A375 cells were not. However, A375 cells acquired resistance upon <i>ALDH2</i> knockout. Furthermore, melanoma cells with acquired resistance to these inhibitors displayed further ALDH2 downregulation. Our findings indicate that <i>ALDH2</i> downregulation contributes to melanoma progression and therapy resistance in <i>BRAF</i>-mutated human metastatic melanoma cells, highlighting ALDH2 as a potential prognostic marker and therapeutic target in metastatic melanoma.