The Long Non-Coding RNA SNHG12 as a Mediator of Carboplatin Resistance in Ovarian Cancer via Epigenetic Mechanisms

SIMPLE SUMMARY: Epithelial ovarian cancer is a lethal malignancy in which recurrence and therapy resistance are the major causes of death. We investigated the transcriptome and DNA methylation profile of ovarian cancer cell lines sensitive and resistant to carboplatin, aiming to identify genes associated with therapy resistance. We focused on long non-coding RNAs (lncRNAs), known as epigenetic regulators of several cellular and biological processes. We found 11 lncRNAs associated with carboplatin resistance, including SNHG12 (small nucleolar RNA host gene 12), also confirmed in an external dataset (The Cancer Genome Atlas). SNHG12 gene silencing increased the sensitivity to carboplatin, giving evidence that this lncRNA contributes to resistance to carboplatin in ovarian cancer cell lines. We also demonstrated that SNHG12 could control the expression of nearby genes probably by altering epigenetic markers and modifying the transcript levels. ABSTRACT: Genetic and epigenetic changes contribute to intratumor heterogeneity and chemotherapy resistance in several tumor types. LncRNAs have been implicated, directly or indirectly, in the epigenetic regulation of gene expression. We investigated lncRNAs that potentially mediate carboplatin-resistance of cell subpopulations, influencing the progression of ovarian cancer (OC). Four carboplatin-sensitive OC cell lines (IGROV1, OVCAR3, OVCAR4, and OVCAR5), their derivative resistant cells, and two inherently carboplatin-resistant cell lines (OVCAR8 and Ovc316) were subjected to RNA sequencing and global DNA methylation analysis. Integrative and cross-validation analyses were performed using external (The Cancer Genome Atlas, TCGA dataset, n = 111 OC samples) and internal datasets (n = 39 OC samples) to identify lncRNA candidates. A total of 4255 differentially expressed genes (DEGs) and 14529 differentially methylated CpG positions (DMPs) were identified comparing sensitive and resistant OC cell lines. The comparison of DEGs between OC cell lines and TCGA-OC dataset revealed 570 genes, including 50 lncRNAs, associated with carboplatin resistance. Eleven lncRNAs showed DMPs, including the SNHG12. Knockdown of SNHG12 in Ovc316 and OVCAR8 cells increased their sensitivity to carboplatin. The results suggest that the lncRNA SNHG12 contributes to carboplatin resistance in OC and is a potential therapeutic target. We demonstrated that SNHG12 is functionally related to epigenetic mechanisms.