NOC2L Promotes Paclitaxel Resistance in Various Types of Ovarian Cancers by Decreasing NDUFA4 through Histone Acetylation Suppression.

Abstract

Ovarian cancer is a common malignant tumor in the female reproductive system. Paclitaxel resistance is the primary cause of treatment failure in patients with ovarian cancer. Therefore, elucidating the mechanisms by which ovarian cancer develops paclitaxel resistance is crucial for achieving better therapeutic outcomes. This study analyzed data from the GSE50831 dataset (the response of 21 ovarian cancer cell lines to paclitaxel), the GSE26193 dataset (the progression of 107 patients with ovarian cancer), and the Ovarian Cancer Genome Atlas. Key differentially expressed genes were selected through intersection analysis, least absolute shrinkage and selection operator, 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 ovarian cancer cells. Data from these datasets showed that NOC2L was upregulated in all ovarian cancer 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 ovarian cancer cell resistance to paclitaxel. The Ovarian Cancer Genome Atlas 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, by suppressing histone acetylation, resulting in a remodeling of energy metabolism toward aerobic glycolysis. Collectively, NOC2L inducing energy metabolism to aerobic glycolysis is a consistent mechanism in various ovarian cancer cells resistant to paclitaxel. Hence, NOC2L is a promising target to improve the sensitivity of ovarian cancer cells to paclitaxel.