---
title: "Inhibiting the MAT2A–SAM Axis Enhances Platinum Sensitivity in Ovarian Cancer by Disrupting DNA Re"
id: "biorxiv-9-targeting-mat2a-s-adenosylmethionine-sam-axis-attenuates-dna-damage-response"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-9-targeting-mat2a-s-adenosylmethionine-sam-axis-attenuates-dna-damage-response"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.22.753550v1?rss=1"
published_at: "2026-09-23T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Inhibiting the MAT2A–SAM Axis Enhances Platinum Sensitivity in Ovarian Cancer by Disrupting DNA Re
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-9-targeting-mat2a-s-adenosylmethionine-sam-axis-attenuates-dna-damage-response
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.22.753550v1?rss=1)
- **Published At:** 2026-09-23T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Metabolic and epigenetic reprogramming drive platinum resistance and recurrence in high-grade serous ovarian cancer (HGSC). The authors investigated the role of **MAT2A**-driven synthesis of **S-adenosylmethionine (SAM)** in this process. - MAT2A converts methionine to SAM, the universal methyl donor; prior work linked SAM-dependent DNA methylation changes to acquired platinum resistance in HGSC. - The study found that **MAT2A upregulation correlated with poorer progression-free survival** in ovarian cancer patients reported in the source. - Both pharmacologic inhibition and genetic knockdown of **MAT2A** increased sensitivity to cisplatin in experimental models. - Genome-wide DNA methylation profiling in OVCAR3 cells treated with cisplatin (15 μM, 16 hr) and/or MAT2A siRNA (48 hr) showed that **MAT2A knockdown reversed platinum-induced DNA methylation changes**, with pathway enrichment for platinum resistance, DNA repair, and stemness. - Inhibiting MAT2A prevented platinum-induced promoter hypermethylation and disrupted the **SAMTOR–mTOR–S6K–FANCD2** signaling axis, leading to accumulation of R-loops and impaired activation of DNA repair after platinum exposure. - Functional DNA damage reporter assays demonstrated that MAT2A knockdown reduced repair by both **homologous recombination (HR)** and **non-homologous end joining (NHEJ)** pathways. - Detection of DNA damage response kinases showed that **MAT2A inhibition abrogated DNA repair activation** in response to platinum, resulting in increased DNA damage and cell death when combined with cisplatin. - Single-sample Gene Set Enrichment Analysis (ssGSEA) of paired primary and recurrent HGSC tumors associated **MAT2A expression with increased ovarian cancer stem cell (OCSC)** features in recurrent tumors. - In vitro, MAT2A inhibition blocked cisplatin-induced enrichment of OCSCs, decreased stemness markers, and reduced spheroid-forming ability; these effects were rescued by **SAM supplementation**, indicating dependence on SAM availability. - Overall, the preprint proposes the **MAT2A–SAM axis** as a therapeutic target to enhance platinum sensitivity by attenuating DNA damage response and OCSC enrichment, potentially reducing OCSC-driven recurrence in HGSC. - This work is a preprint and has not been peer reviewed; methodological details beyond those reported in the abstract (for example, specific inhibitors, full patient cohort descriptions, or statistical values) were not provided in the source text.
## Clinical Analysis & Structured Key Points
Targeting MAT2A-S-adenosylmethionine (SAM) Axis Attenuates DNA Damage Response and Cancer Stemness to Increase Platinum Sensitivity in Ovarian Cancer | bioRxiv Skip to main content New Results Targeting MAT2A-S-adenosylmethionine (SAM) Axis Attenuates DNA Damage Response and Cancer Stemness to Increase Platinum Sensitivity in Ovarian Cancer View ORCID Profile Shu Zhang , Zhen Fu , Yanchi Zhou , Tara X Metcalfe , Truc T Vuong , Lindsay W Brubaker , View ORCID Profile Benjamin G Bitler , View ORCID Profile Heather M O'Hagan , Kenneth P. Nephew doi: https://doi.org/10.64898/2026.09.22.753550 Shu Zhang 1 Indiana University Bloomington; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Shu Zhang Zhen Fu 2 Van Andel Institute, Grand Rapids, MI; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yanchi Zhou 1 Indiana University Bloomington; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tara X Metcalfe 3 Indiana University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Truc T Vuong 1 Indiana University Bloomington; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lindsay W Brubaker 4 University of Colorado Anschutz Medical Campus; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Benjamin G Bitler 5 The University of Colorado; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Benjamin G Bitler Heather M O'Hagan 6 Indiana University School of Medicine Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Heather M O'Hagan Kenneth P. Nephew 6 Indiana University School of Medicine Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: knephew{at}iu.edu Abstract Info/History Metrics Supplementary material Preview PDF Abstract 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 (15μM, 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. Competing Interest Statement The authors have declared no competing interest. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Posted September 23, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Targeting MAT2A-S-adenosylmethionine (SAM) Axis Attenuates DNA Damage Response and Cancer Stemness to Increase Platinum Sensitivity in Ovarian Cancer Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Targeting MAT2A-S-adenosylmethionine (SAM) Axis Attenuates DNA Damage Response and Cancer Stemness to Increase Platinum Sensitivity in Ovarian Cancer Shu Zhang , Zhen Fu , Yanchi Zhou , Tara X Metcalfe , Truc T Vuong , Lindsay W Brubaker , Benjamin G Bitler , Heather M O'Hagan , Kenneth P. Nephew bioRxiv 2026.09.22.753550; doi: https://doi.org/10.64898/2026.09.22.753550 Share This Article: Copy Citation Tools Targeting MAT2A-S-adenosylmethionine (SAM) Axis Attenuates DNA Damage Response and Cancer Stemness to Increase Platinum Sensitivity in Ovarian Cancer Shu Zhang , Zhen Fu , Yanchi Zhou , Tara X Metcalfe , Truc T Vuong , Lindsay W Brubaker , Benjamin G Bitler , Heather M O'Hagan , Kenneth P. 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