PO.TB07.02 · 肿瘤生物学
NQO1抑制FBXL14依赖的SNAIL降解，从而在结直肠癌细胞中促进EMT介导的干性
NQO1 inhibits FBXL14-dependent SNAIL degradation to promote EMT-mediated stemness in colorectal cancer cells
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
NAD(P)H:醌氧化还原酶1（NQO1）的过表达与多种人类癌症的不良预后相关。在结直肠癌（CRC）中，NQO1过表达常与肿瘤进展和癌症干细胞（CSC）的形成相关，后者可通过其自我更新和分化能力驱动治疗耐药、复发和转移。然而，NQO1调控CSC特性的确切机制仍知之甚少。在此，我们研究了NQO1在调节人CRC细胞CSC特性中的功能。在CRC细胞系中敲低NQO1显著减少了结肠球形成，并下调了关键干性相关标志物基因Nanog、Oct4和Sox2。相反，在NQO1敲低的细胞系中恢复NQO1表达可挽救结肠球形成并恢复这些CSC标志物基因的水平。进一步研究揭示，NQO1的调节改变了Snail的表达和稳定性，Snail是参与CSC维持的关键转录因子。抑制NQO1下调了Snail及其靶向的CSC标志物基因。研究发现NQO1直接结合Snail的核输出信号（NES）结构域，以阻止其与E3泛素连接酶FBXL14的相互作用，后者靶向Snail使其经蛋白酶体降解。这种保护性相互作用稳定了Snail并增强了其下游干性相关的转录活性。与这些结果一致，NQO1敲低增强了CRC细胞对5-FU和电离辐射的敏感性。重要的是，Snail过表达部分恢复了NQO1抑制细胞对这些治疗的耐药性，表明NQO1通过稳定Snail促进治疗耐药。对临床CRC数据集的分析表明，NQO1与Snail靶向的CSC标志物基因表达之间存在强正相关，并且这与CRC患者的不良预后进一步相关。我们的研究结果共同表明，NQO1通过稳定Snail促进CRC干性和患者不良预后。因此，靶向NQO1可能代表一种有前景的治疗策略，以消除CSC并改善CRC的治疗结局。
查看英文原文 English 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.
利益披露 Disclosure
H. Kim, None..
Y. Cho, None..
E. Oh, None.