Biology subjects

Vuong, T. T.

Publications and source records attributed to Vuong, T. T..

3 recordsLinked to original sources

bioRxiv2026

Targeting MAT2A-S-adenosylmethionine (SAM) Axis Attenuates DNA Damage Response and Cancer Stemness to Increase Platinum Sensitivity in Ovarian Cancer

Abstract Metabolic and epigenetic reprogramming drives development of platinum resistance and disease recurrence in high-grade serous ovarian cancer (HGSC), a major clinical challenge in the field. S-adenosylmethionine (SAM) is the universal methyl group donor, synthesized by methionine adenosyltransferase 2A (MAT2A) from methionine. Prior studies have linked altered SAM-dependent DNA methylation to acquired platinum resistance in HGSC, connecting metabolism and epigenetic regulation. However, how MAT2A-driven SAM synthesis coordinates the metabolic-epigenetic remodeling axis to affect platinum sensitivity remains unclear. Here, we report that MAT2A-driven SAM synthesis is required for platinum-induced alterations in DNA methylation and the enrichment of ovarian cancer stem cells (OCSCs). We found that MAT2A upregulation correlated with poor progression-free survival in OC patients, and both pharmacological inhibition and genetic knockdown of MAT2A increased sensitivity to cisplatin. To investigate the underlying epigenetic mechanism, we profiled genome-wide changes in DNA methylation using OVCAR3 treated with cisplatin (15M, 16hr) and/or MAT2A siRNA (48hr), which showed that MAT2A knockdown reversed platinum-induced DNA methylation dynamics. Subsequent analysis revealed enrichment of pathways associated with platinum resistance, DNA repair, and stemness. Mechanistically, inhibiting MAT2A abrogated both the platinum-induced hypermethylation at promoter regions and the SAMTOR-mTOR-S6K-FANCD2 signaling axis, resulting in accumulated R-loops, attenuated DNA repair activation in response to platinum, and enhanced platinum-induced DNA damage and cell death. Using a functional DNA damage reporter assay, we directly showed that MAT2A knockdown reduced DNA repair through homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. By detecting key DNA damage response kinases governing HR and NHEJ signaling, we further demonstrated that MAT2A inhibition abrogated DNA repair activation in response to platinum. Furthermore, single-sample Gene Set Enrichment Analysis of paired primary and recurrent tumors from HGSC patients revealed an association between MAT2A expression and increased OCSC features in recurrent tumors. In vitro, MAT2A inhibition prevented cisplatin-induced enrichment of OCSCs, reduced stemness markers, and inhibited spheroid-forming ability, all of which were rescued by SAM supplementation. Together, our study reveals a previously unrecognized mechanism linking metabolism to epigenetic regulation through platinum-induced remodeling and establishes the MAT2A-SAM axis as a promising therapeutic target to enhance platinum sensitivity by abrogating DNA damage response and OCSC enrichment and ultimately reduce OCSC-driven disease recurrence in HGSC.

cancer biology↗

bioRxiv2024

Drosophila ring chromosomes interact with sisters and homologs to produceanaphase bridges in mitosis.

Ring chromosomes are known in many eukaryotic organisms, including humans. They are typically associated with a variety of maladies, including abnormal development and lethality. Underlying these phenotypes are anaphase chromatin bridges that can lead to chromosome loss, nondisjunction and breakage. By cytological examination of ring chromosomes in Drosophila melanogaster we identified five causes for anaphase bridges produced by ring chromosomes. Catenation of sister chromatids is the most common cause and these bridges frequently resolve during anaphase, presumably by the action of topoisomerase II. Sister chromatid exchange and chromosome breakage followed by sister chromatid union also produce anaphase bridges. Mitotic recombination with the homolog was rare, but was another route to generation of anaphase bridges. Most surprising, was the discovery of homolog capture, where the ring chromosome was connected to its linear homolog in anaphase. We hypothesize that this is a remnant of mitotic pairing and that the linear chromosome is connected to the ring by multiple wraps produced through the action of topoisomerase II during establishment of homolog pairing. In support, we showed that in a ring/ring homozygote the two rings are frequently catenated in mitotic metaphase, a configuration that requires breaking and rejoining of at least one chromosome.

genetics↗

bioRxiv2023

Activation of AKT induces EZH2-mediated beta-catenin trimethylation in colorectal cancer

Colorectal cancer (CRC) develops in part through the deregulation of different signaling pathways, including activation of the WNT/{beta}-catenin and PI3K/AKT pathways. Enhancer of zeste homolog 2 (EZH2) is a lysine methyltransferase that is involved in regulating stem cell development and differentiation and is overexpressed in CRC. However, depending on the study EZH2 has been found to be both positively and negatively correlated with the survival of CRC patients suggesting that EZH2s role in CRC may be context specific. In this study, we explored how PI3K/AKT activation alters EZH2s role in CRC. We found that activation of AKT by PTEN knockdown or by hydrogen peroxide treatment induced EZH2 phosphorylation at serine 21. Phosphorylation of EZH2 resulted in EZH2-mediated methylation of {beta}-catenin and an associated increased interaction between {beta}-catenin, TCF1, and RNA polymerase II. AKT activation increased {beta}-catenins enrichment across the genome and EZH2 inhibition reduced this enrichment by reducing the methylation of {beta}-catenin. Furthermore, PTEN knockdown increased the expression of epithelial-mesenchymal transition (EMT)-related genes, and somewhat unexpectedly EZH2 inhibition further increased the expression of these genes. Consistent with these findings, EZH2 inhibition enhanced the migratory phenotype of PTEN knockdown cells. Overall, we demonstrated that EZH2 modulates AKT-induced changes in gene expression through the AKT/EZH2/ {beta}-catenin axis in CRC with active PI3K/AKT signaling. Therefore, it is important to consider the use of EZH2 inhibitors in CRC with caution as these inhibitors will inhibit EZH2-mediated methylation of histone and non-histone targets such as {beta}-catenin, which can have tumor-promoting effects.

cancer biology↗