NOC2L promotes paclitaxel resistance in various types of ovarian cancers by decreasing NDUFA4 through histone acetylation suppression.

Abstract

Ovarian cancer (OC) is a common malignant tumor in the female reproductive system. Paclitaxel resistance is the primary cause of treatment failure in patients with OC. Therefore, elucidating the mechanisms by which OC develops paclitaxel resistance is crucial for achieving better therapeutic outcomes. This study analyzed data from GSE50831 (the response of 21 OC cell lines to paclitaxel), GSE26193 (the progression of 107 patients with OC) datasets, and the Ovarian Cancer Genome Atlas (TCGA). Key differentially expressed genes were selected through intersection analysis, Least Absolute Shrinkage And Selection Operator (LASSO), and multivariate Cox regression analysis. Experiments were conducted to validate the candidate gene, NOC2L, and explore its role in the development of paclitaxel resistance in OC cells. Data from these datasets showed that NOC2L was upregulated in all OC cell lines after paclitaxel treatment, and this upregulation was associated with poorer patient progression. Both loss- and gain-of-function experiments confirmed that NOC2L promotes OC cell resistance to paclitaxel. The TCGA dataset showed that NOC2L is negatively correlated with the NADH:Ubiquinone oxidoreductase core subunit family (NDUF) proteins: NDUFB4, NDUFA1, NDUFS4, NDUFB1, NDUFA2, NDUFA4, and MT-ND3. Studies have revealed that NOC2L decreases the expression of NDUF proteins, particularly NDUFA4, via suppressing histone acetylation, resulting in a remodeling of energy metabolism towards aerobic glycolysis. Collectively, NOC2L inducing energy metabolism to aerobic glycolysis is a consistent mechanism in various OC cells resistant to paclitaxel. NOC2L, hence, is a promising target to improve the sensitivity of OC cells to paclitaxel.