OGDHL regulates nucleotide metabolism, tumor growth, and neuroendocrine marker expression in prostate cancer

Bernard, M.; Ruiz, A.; Diaz, J.; Nunley, N.; Dove, R.; Heering, K.; Bopardikar, S.; Gallardo, A.; Hashimoto, T.; Agrawal, R.; Smith, C.; Wilde, B.; Matulionis, N.; Richards, H.; Sharifi, M.; Lang, J.; Zhao, S.; Haffner, M.; Boutros, P. C.; Christofk, H.; Goldstein, A. S.

doi:10.1101/2025.05.28.656673

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bioRxiv · 10.1101/2025.05.28.656673

OGDHL regulates nucleotide metabolism, tumor growth, and neuroendocrine marker expression in prostate cancer

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Abstract

As cancer cells evade therapeutic pressure and adopt alternate lineage identities not commonly observed in the tissue of origin, they likely adopt alternate metabolic programs to support their evolving demands. Targeting these alternative metabolic programs in distinct molecular subtypes of aggressive prostate cancer may lead to new therapeutic approaches to combat treatment-resistance. We identify the poorly studied metabolic enzyme Oxoglutarate Dehydrogenase-Like (OGDHL), named for its structural similarity to the tricarboxylic acid (TCA) cycle enzyme Oxoglutarate Dehydrogenase (OGDH), as an unexpected regulator of tumor growth, treatment-induced lineage plasticity, and DNA Damage in prostate cancer. While OGDHL has been described as a tumor-suppressor in various cancers, we find that its loss impairs prostate cancer cell proliferation and tumor formation. Loss of OGDHL profoundly alters Androgen Receptor inhibition-induced plasticity, including suppressing the neuroendocrine markers DLL3 and HES6, induces accumulation of the DNA damage response marker {gamma}H2AX, and reduces nucleotide synthesis. Our data suggest that OGDHL has minimal impact on TCA cycle activity, and that mitochondrial localization is not required for its regulation of prostate cancer plasticity and nucleotide metabolism. Finally, we demonstrate that OGDHL expression is tightly correlated with neuroendocrine differentiation in clinical prostate cancer. These findings underscore the importance of investigating poorly characterized metabolic genes as potential regulators of distinct molecular subtypes of aggressive cancer.

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Bernard, M., Ruiz, A., Diaz, J., Nunley, N., Dove, R., Heering, K., Bopardikar, S., Gallardo, A., Hashimoto, T., Agrawal, R., Smith, C., Wilde, B., Matulionis, N., Richards, H., Sharifi, M., Lang, J., Zhao, S., Haffner, M., Boutros, P. C., Christofk, H., Goldstein, A. S.. 2025-06-01. OGDHL regulates nucleotide metabolism, tumor growth, and neuroendocrine marker expression in prostate cancer. https://doi.org/10.1101/2025.05.28.656673

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