Biology subjects

Soldan, S. S.

Publications and source records attributed to Soldan, S. S..

3 recordsLinked to original sources

bioRxiv2025

Integrated transcriptomic and methylome analysis reveals retinoic acid pathway activation after decitabine treatment in EBV associated gastric cancer

Epstein-Barr virus associated gastric cancer (EBVaGC) accounts for [~]9-10% of gastric cancers worldwide and is defined by a distinctive molecular profile, including extreme hypermethylation of the DNA. Targeting this aberrant methylation may be a potential therapeutic strategy. EBV+ gastric cancer cell lines (YCCEL1, SNU719) and EBV- lines (AGS, SNU16, MKN74) were treated with a DNA methyl-transferase inhibitor (DNMT), decitabine (DCB), for three days followed by RNA sequencing to identify EBV-specific responses. DNA methylation profiling by reduced representation bisulfite sequencing (RRBS) was performed in EBV+ cell-lines and integrated with expression data to identify epigenetically regulated networks. While DCB induced broad transcriptional changes across all lines, EBV+ cells exhibited the strongest transcriptional response, sharing many upregulated genes. Many of these EBV+ specific genes were expressed at lower baseline levels in EBV+ tumors from TCGA. DCB predominantly reduced methylation at highly methylated intergenic CpGs, with a subset of promoters undergoing significant demethylation. Integrated analysis revealed a strong inverse correlation between promoter demethylation and gene expression, implicating multiple cancer-relevant pathways. Upstream regulator analysis and motif enrichment indicated that regions losing methylation were enriched for retinoic acid receptor (RAR) binding motifs, suggesting that DCB-mediated demethylation restores RA pathway accessibility and transcriptional activity. Further, inhibiting RAR signaling reduced DCB induced apoptosis. Although DCB can induce both host gene re-expression and viral lytic gene activation in EBV-positive tumors, its impact on RA signaling in EBVaGC has not been studied. Decitabine promotes extensive epigenetic reprogramming in EBVaGC, with preferential effects in CIMP-positive, EBV-infected cell lines. ImportanceEBV+ gastric cancer contains hypermethylated DNA and despite this distinct molecular phenotype there are currently no EBV-specific treatments available. Using an FDA approved inhibitor to target hypermethylated DNA and multi-omics approach to study the cellular response, we uncovered epigenetically altered transcriptional networks that may be further exploited to improve potential therapy. Among the pathways disrupted, retinoic acid signaling is of particular interest, as retinoid receptors such as RAR and RAR{beta} are frequently hypermethylated and repressed in EBVaGC. Our findings indicate that DNMT inhibition can partially reverse RA receptor silencing, supporting further investigation of DNMTi-RA combination strategies as a novel therapy for EBV+ gastric cancer.

microbiology↗

bioRxiv2023

PARP1 Inhibition Halts EBV+ Lymphoma Progression by Disrupting the EBNA2/MYC Axis

PARP1 has been shown to regulate EBV latency. However, the therapeutic effect of PARP1 inhibitors on EBV+ lymphomagenesis has not yet been explored. Here, we show that PARPi BMN-673 has a potent anti-tumor effect on EBV-driven LCL in a mouse xenograft model. We found that PARP1 inhibition induces a dramatic transcriptional reprogramming of LCLs driven largely by the reduction of the MYC oncogene expression and dysregulation of MYC targets, both in vivo and in vitro. PARP1 inhibition also reduced the expression of viral oncoprotein EBNA2, which we previously demonstrated depends on PARP1 for activation of MYC. Further, we show that PARP1 inhibition blocks the chromatin association of MYC, EBNA2, and tumor suppressor p53. Overall, our study strengthens the central role of PARP1 in EBV malignant transformation and identifies the EBNA2/MYC pathway as a target of PARP1 inhibitors and its utility for the treatment of EBNA2-driven EBV-associated cancers. Significance StatementA promising approach to treating EBV-driven malignancies involves targeting cancer and EBV biology. However, investigating host factors that co-regulate EBV latent gene expression, such as PARP1, has been incomplete. Our study demonstrates that the PARP1 inhibitor BMN-673 effectively reduces EBV-driven tumors and metastasis in an LCL xenograft model. Additionally, we have identified potential dysregulated mechanisms associated with PARP1 inhibition. These findings strengthen the role of PARP1 in EBV+ lymphomas and establish a link between PARP1 and the EBNA2/MYC axis. This has important implications for developing therapeutic approaches to various EBV-associated malignancies.

cancer biology↗

bioRxiv2022

Regulation of EBNA1 Protein Stability by PLOD1 Lysine Hydroxylase

Epstein-Barr virus (EBV) is a ubiquitous human {gamma}-herpesvirus that is causally associated with various malignancies and autoimmune disease. Epstein-Barr Nuclear Antigen 1 (EBNA1) is the viral-encoded DNA binding protein required for viral episome maintenance and DNA replication during latent infection in proliferating cells. EBNA1 is known to be a highly stable protein, but its mechanism of protein stability is not completely understood. Proteomic analysis of EBNA1 revealed interaction with Procollagen Lysine-2 Oxoglutarate 5 Dioxygenase (PLOD) family of proteins. Depletion of PLOD1 by shRNA or inhibition with small molecule inhibitors 2,-2 dipyridyl resulted in the loss of EBNA1 protein levels, along with a selective growth inhibition of EBV-positive lymphoid cells. PLOD1 depletion also caused a loss of EBV episomes from latently infected cells and inhibited oriP-dependent DNA replication. We used mass spectrometry to identify EBNA1 peptides with lysine hydroxylation at K460 or K461. Mutation of K460 to alanine or arginine abrogates EBNA1-driven DNA replication of oriP, while K461 mutations enhanced replication. These findings suggest that PLOD1 is a novel post-translational regulator of EBNA1 protein stability and function in viral plasmid replication, episome maintenance and host cell survival. ImportanceEBNA1 is essential for EBV latent infection and implicated in viral pathogenesis. We found that EBNA1 interacts with PLOD family of lysine hydroxylases and that this interaction is required for EBNA1 protein stability and function in viral persistence during viral latent infection. Identification of PLOD1 regulation of EBNA1 protein stability provide new opportunity to target EBNA1 for degradation in EBV associated disease.

molecular biology↗