Abstract 2191: NQO1 inhibits FBXL14-dependent SNAIL degradation to promote EMT-mediated stemness in colorectal cancer cells.

Abstract Overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1) is associated with poor prognosis in various human cancers. In colorectal cancer (CRC), NQO1 overexpression is frequently associated with tumor progression and the formation of cancer stem cells (CSCs), which can drive therapy resistance, recurrence, and metastasis via their self-renewal and differentiation capacities. However, the precise mechanisms by which NQO1 regulates CSC traits remain poorly understood. Here, we investigated the functions of NQO1 in modulating CSC properties in human CRC cells. Knockdown of NQO1 in CRC cell lines markedly reduced colonosphere formation and downregulated the key stemness-related marker genes, Nanog, Oct4, and Sox2. Conversely, restoration of NQO1 expression in NQO1-knockdown cell lines rescued colonosphere-formation and restored the levels of these CSC marker genes. Further investigation revealed the modulation of NQO1 changed the expression and stability of Snail, a key transcription factor involved in CSC maintenance. Suppression of NQO1 downregulated Snail and its targeted CSC marker genes. NQO1 was found to directly bind the nuclear export signal (NES) domain of Snail to prevent its interaction with the E3 ubiquitin ligase FBXL14, which targets Snail for proteasomal degradation. This protective interaction stabilized Snail and enhanced its downstream stemness-related transcriptional activity. In line with these results, NQO1 knockdown enhanced the sensitivity of CRC cells to 5-FU and ionizing radiation. Importantly, Snail overexpression partially restored the resistance to these treatments in NQO1-suppressed cells, suggesting that NQO1 promotes therapy resistance by stabilizing Snail. Analysis of clinical CRC datasets demonstrated that there is a strong positive correlation between NQO1 and Snail-targeted CSC marker gene expression, and this was further correlated with poor prognosis in CRC patients. Our findings collectively suggest that NQO1 promotes CRC stemness and poor patient prognosis by stabilizing Snail. Targeting NQO1 may therefore represent a promising therapeutic strategy to eliminate CSCs and improve treatment outcomes in CRC. Citation Format: Ha Gyeong Kim, Yunmi Cho, Eun-Taex Oh. NQO1 inhibits FBXL14-dependent SNAIL degradation to promote EMT-mediated stemness in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2191.