Dhodh Links Mitochondrial Bioenergetics, One-Carbon Metabolism, and DNA Repair To Sustain Aggressive Prostate Adenocarcinoma

Authors

• Saiswaroop Rajaratnam
• Danthasinghe Waduge Badrajee Piyarathna
• Ranjit K Mehta
• Venugopalareddy Mekala
• Jun Hyoung Park
• Uttam Rasaily
• Vani Venkatappa
• Karthik Reddy Kami Reddy
• Vasanta Putluri
• Kaveri Goel
• Sandra L Grimm
• Sai Manohar Thota
• Taylor Morrison
• Cristian Coarfa
• Benny Abraham Kaipparettu
• Chao Cheng
• Nagireddy Putluri
• Jeffrey A Jones
• Mukesh K Nyati
• Michael Ittmann
• Natalie R Gassman
• Arun Sreekumar

Language

English

Publication Date

1-29-2026

Journal

Cell Communication and Signaling

DOI

10.1186/s12964-026-02691-9

PMID

41612476

PMCID

PMC12930642

PubMedCentral® Posted Date

1-29-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Background

Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that connects de novo pyrimidine biosynthesis with the electron transport chain (ETC) function. However, its broader role in prostate cancer (PCa) signaling and response to therapy remains unclear.

Methods

We combined transcriptomic, metabolomic, epigenomic, and functional analyses with clinical outcome data to explore the effects of DHODH depletion in ancestry-annotated European American (EA) and African American (AA) prostate cancer cell line models.

Results

DHODH was markedly overexpressed in malignant prostate epithelial cells and was abundant in tumors. Its knockdown hindered cell proliferation by causing pyrimidine depletion, while unexpectedly increasing oxidative phosphorylation, ETC complex activity through metabolic stress–driven mitochondrial biogenesis. This also led to oxidative stress due to an imbalance in NADP⁺/NADPH. Metabolomics indicated enhanced one-carbon metabolism and increased overall DNA methylation. Whole-genome bisulfite sequencing of DHODH KD cells identified regions with differential methylation in genes related to epithelial–mesenchymal transition (EMT) and inflammatory signaling. Functionally, the loss of DHODH decreased cell migration and metastasis and downregulated genes involved in nucleotide excision repair, mismatch repair, and base excision repair.

Additionally, it upregulated a subset of Y-family DNA polymerases, which facilitate error-prone lesion bypass. This was associated with more unrepaired DNA damage and, paradoxically, higher clonogenic survival under genotoxic stress. Clinically, low DHODH expression was linked to shorter biochemical recurrence–free survival after radiotherapy combined with androgen deprivation therapy.

Conclusions

DHODH functions as a crucial regulator of metabolism, epigenetics, and genomics in prostate cancer, coordinating mitochondrial respiration, one-carbon metabolism, and DNA repair signaling to promote tumor growth and improve treatment outcomes. Its absence introduces vulnerabilities in genome stability, supporting the idea of combining DHODH inhibitors with DNA repair–targeted therapies for the treatment of prostate cancer.

Keywords

DHODH, Prostate adenocarcinoma, Mitochondria, Methylation, DNA repair

Published Open-Access

yes

Recommended Citation

Rajaratnam, Saiswaroop; Piyarathna, Danthasinghe Waduge Badrajee; Mehta, Ranjit K; et al., "Dhodh Links Mitochondrial Bioenergetics, One-Carbon Metabolism, and DNA Repair To Sustain Aggressive Prostate Adenocarcinoma" (2026). Faculty, Staff and Students Publications. 6934.
https://digitalcommons.library.tmc.edu/baylor_docs/6934