Epigenetically Downregulated Breast Cancer Gene 2 through Acetyltransferase Lysine Acetyltransferase 2B Increases the Sensitivity of Colorectal Cancer to Olaparib.

Olaparib suppresses DNA damage repair by inhibiting the poly ADP ribose polymerase (PARP), especially in cancers with BRCA1/2 mutations or the BRCA-ness phenotype. However, the first trials showed that some patients with defective DNA damage repair are still resistant to olaparib. The recovery of the wildtype BRCA is a prominent mechanism of PARP inhibitor (PARPi) resistance in BRCA-deficient tumors, but additional molecular features of olaparib resistance remain poorly understood. The objective of our study was to find molecular parameters that contribute to olaparib response or resistance in CRC. We report that histone acetyltransferase KAT2B decreases BRCA2 expression by reducing the acetylation of the 27th amino acid in histone H3 (H3K27) at the promoter of the BRCA2 gene in colorectal cancer (CRC). This increases the sensitivity of CRC cells toward olaparib treatment. The H3K27ac binding domain of BRCA2 may be required for its transcription. Low endogenous KAT2B expression, which we identify in a subset of cultured BRCA2-expressing CRC cells, leads to an accumulation of γH2AX (more DNA damage), resulting in low PARPi resistance in BRCA-expressing cells. Our results reveal KAT2B and histone acetylation as regulators of BRCA2 expression and PARPi responses in BRCA2-expressing CRC cells, providing further insights into molecular prerequisites for targeting BRCA-functional tumors.

H19 encourages aerobic glycolysis and cell growth in gastric cancer cells through the axis of microRNA-19a-3p and phosphoglycerate kinase 1.

Numerous studies have been conducted on long non-coding RNAs (lncRNAs) in human tumors like gastric cancer (GC). Our research uncovers how aerobic glycolysis and cell proliferation in gastric cancer cells are related to H19. We discovered that H19 was highly expressed in tumor tissues and that patients with higher H19 expression have a poorer prognosis. Intriguingly, we applied the subcellular isolation, luciferase reporter, western blot analysis, MTT, colony formation experiments, and CDX Model in Mice to verify that H19 regulates aerobic glycolysis towards GC cell growth by H19/microRNA (miR)-19a-3p/phosphoglycerate kinase 1 (PGK1) axis. Together, our research offers proof that the H19/miR-19a-3p/PGK1 pathway aids in the regulation of aerobic glycolysis and cell proliferation in GC. This may offer an opportunity for novel therapeutic approaches to the treatment of GC.

Expression profile of lncRNAs and mRNAs in intestinal macrophages.

Non-coding RNAs (ncRNAs) have been previously reported to serve an important role in transcription. In addition, several studies have revealed that long ncRNAs (lncRNAs) have a crucial role in human diseases. However, the association between lncRNAs and inflammation­induced intestinal macrophages in the intestinal mucosal barrier has remained elusive. In the present study, intestinal macrophages from healthy Sprague Dawley rats were divided into two groups: The experimental group, consisting of intestinal macrophages treated with 1 mg/l lipopolysaccharide (LPS) and the control group, composed of untreated cells. Differentially expressed (DE) lncRNAs and mRNAs between the control and experimental groups were identified using microarray profiling. The levels of DE mRNAs and lncRNAs were measured by reverse transcription­quantitative PCR (RT­qPCR). Furthermore, Gene Ontology (GO) and pathway enrichment analyses of DE mRNAs and lncRNAs were performed. To identify core regulatory factors among DE lncRNAs and mRNAs, a lncRNA­mRNA network was constructed. A total of 357 DE lncRNAs and 542 DE mRNAs between the LPS­treated and untreated groups were identified (fold-change >1.5; P<0.05). In addition, selected microarray data were confirmed by RT­qPCR. GO analysis of the DE mRNAs indicated that the biological functions of the upregulated mRNAs included inflammatory response, immune response, metabolic process and signal transduction, whereas those of the downregulated mRNAs were metabolic process, cell cycle, apoptosis and inflammatory response. In addition, pathway enrichment analysis of the upregulated mRNAs revealed that the most enriched pathways were the NF­κB signaling pathway, B­cell receptor signaling pathway and apoptosis, while the downregulated mRNAs were significantly involved in metabolic pathways, the phosphatidylinositol signaling system, cytokine­cytokine receptor interaction and the Toll­like receptor signaling pathway. The lncRNA­mRNA co­expression network suggested that lncRNAs NONMMUT024673 and NONMMUT062258 may have an important role in LPS­induced intestinal macrophages. The present study identified the DE profiles between LPS­ and non­LPS­treated intestinal macrophages. These DE lncRNAs and mRNAs may be used as potential targets for attenuating excessive inflammatory response in intestinal mucosal barrier dysfunction.