Genome-wide identification of alternative splicing associated with histone deacetylase inhibitor in cutaneous T-cell lymphomas

Abstract

Cutaneous T-cell lymphomas (CTCLs) are a kind of non-Hodgkin lymphoma that originates from skin, which is difficult to treat with traditional drugs. Human histone deacetylase inhibitors (HDACi) targeted therapy has become a promising treatment strategy in recent years, but some patients can develop resistance to the drug, leading to treatment failure. There are no public reports on whether alternative splicing (AS) and RNA binding proteins (RBP) affect the efficacy of targeted therapy. Using data from the Gene Expression Omnibus (GEO) database, we established a co-change network of AS events and RBP in CTCLs for the first time, and analyzed the potential regulatory effects of RBP on HDACi-related AS events. The dataset GSE132053, which contained the RNA sequence data for 17 HDACi samples, was downloaded and clean reads were aligned to the human GRCh38 genome by hierarchical indexing for spliced alignment of the transcripts, allowing four mismatches. Gene expression levels were evaluated using exons per million fragments mapped for each gene. Student’s t-tests were performed to evaluate the significance of changes in ratios for AS events, and regulated alternative splicing events (RASEs) were defined as events with p values less than 0.05. To sort the differentially expressed genes functional categories, Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were identified using the KOBAS 2.0 server. The regulatory mechanisms of the RASEs and RBPs were evaluated using Pearson’s correlation coefficient. Seven indirect events of HDACi resistance or sensitivity were identified: NIR_5151_RP11-977G19.10, NIR_4557_IRAG2, NIR_11870_SUMO1, NIR_5347_ING4, NIR_17935_DNAJC2, NIR_17974_CBLL1, and NIR_422_SLC50A1. The potential regulatory relationships between RBPs and HDACi-sensitive RASEs were also analyzed. LEPR and HNRNPAO significantly affected NIR_11870_SUMO1, suggesting a potential regulatory relationship. Additionally, CNN1 may regulate NIR_5347_ING4, CNOT3 may regulate NIR_17935_DNAJC2, and DQX1 and LENG9 may regulate NIR_422_SLC5A1. Overall, our findings establish a theoretical foundation for the precise targeted treatment of CTCLs with HDACi.