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

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.

Long noncoding RNAs as therapeutic targets to overcome chemoresistance in ovarian cancer

“…TCGA dataset and internal database were used to validate lncRNA candidates. This study found that 4,255 DEGs and 14,529 DMPs (differentially methylated CpG positions) in carboplatin-resistant cells (Abildgaard et al, 2022). They found that 50 lncRNAs were linked to carboplatin resistance.…”

“…RNA sequencing and global DNA methylation assays were performed in four carboplatin-sensitive ovarian cancer cell lines and their resistant cells, and two ovarian cancer cells (OVCAR8 and Ovc316) with inherent carboplatin-resistant cell lines ( Abildgaard et al, 2022 ). TCGA dataset and internal database were used to validate lncRNA candidates.…”

“…They found that 50 lncRNAs were linked to carboplatin resistance. Moreover, 11 lncRNAs exhibited DMPs, including lncRNA SNHG12 ( Abildgaard et al, 2022 ). Furthermore, depletion of lncRNA SNHG12 promoted carboplatin resistance in OVCAR8 and Ovc316 cells.…”

“…Furthermore, depletion of lncRNA SNHG12 promoted carboplatin resistance in OVCAR8 and Ovc316 cells. Therefore, lncRNA SNHG12 accelerated carboplatin resistance in ovarian cancer ( Abildgaard et al, 2022 ).…”

“…Frontiers in Cell and Developmental Biology frontiersin.org cell lines (Abildgaard et al, 2022). TCGA dataset and internal database were used to validate lncRNA candidates.…”