Clear cell renal cell carcinoma (ccRCC) is a paradigm of epigenetic dysregulation. The characteristic loss of chromosome 3p leads to the inactivation of a constellation of pivotal epigenetic regulators, including PBRM1, SETD2, and BAP1, reshaping the epigenome across multiple layers. This review synthesizes the major epigenetic alterations in ccRCC, encompassing aberrations in chromatin structure, dysregulation of DNA and RNA methylation, deregulated noncoding RNAs, and the accumulation of oncometabolites. Collectively, these changes drive oncogene activation, tumor suppressor silencing, genomic instability, and metabolic reprogramming. We also evaluate the clinical potential of these epigenetic alterations. First, they can serve as noninvasive diagnostic and prognostic biomarkers, particularly through the analysis of DNA methylomes and exosomes in liquid biopsies. Second, these alterations enable a therapeutic strategy-epigenetic synthetic lethality-which exploits vulnerabilities induced by the loss of VHL, BAP1, SETD2, and PBRM1. Such vulnerabilities are selectively targetable by PARP, ATR, or EZH2 inhibitors, thereby offering a novel framework for precision medicine in ccRCC. Finally, we outline future research directions, including dissecting intra-tumoral epigenetic heterogeneity, defining functional epigenetic biomarkers, expanding next-generation epigenetic therapeutics, targeting the metabo-epigenetic circuitry, and rationally integrating epigenetic modulators with immunotherapies and HIF-2α inhibitors, aiming to translate epigenetic knowledge into improved clinical outcomes.
BACKGROUND Rituximab resistance remains a major issue in diffuse large B-cell lymphoma (DLBCL), especially the ABC subtype. This study aimed to characterize the transcriptomic and DNA methylation alterations in rituximab‑resistant ABC-type DLBCL cell lines. RESEARCH DESIGN AND METHODS Rituximab-resistant cell lines were generated from ABC (NU-DUL-1-R) and GCB (SU-DHL-6-R) subtypes using stepwise concentration escalation and were validated by flow cytometry-based complement-dependent cytotoxicity (CDC) and antibody‑dependent cellular cytotoxicity (ADCC) assays, as well as CD20, CD55, and CD59 expression. Transcriptome sequencing and 850K methylation array analysis were performed on parental and resistant NU-DUL-1 cells. Differentially expressed genes and methylated positions were identified, followed by enrichment analyses and integrated analysis. RESULTS Both resistant cells showed significantly reduced CDC and CD20 downregulation. NU-DUL-1-R cells exhibited impaired ADCC, whereas SU-DHL-6-R cells retained ADCC, but upregulated CD55 and CD59. Integrated analysis identified eight genes (PLD4, MS4A7, FCRL5, PREX1, RASGRP3, ADAM28, RINL, TINAGL1) in NU-DUL-1-R cells with concordant changes in DNA methylation and mRNA expression. Enrichment analysis implicated cAMP, MAPK and PI3K-Akt-mTOR pathways in rituximab-resistance. CONCLUSIONS This study provides a preliminary characterization of rituximab-resistant ABC-DLBCL cell lines in vitro. The identified subtype-specific mechanisms and candidate genes support further exploration for personalized and epigenetic-targeted therapies.
