Ketone drink enhances therapeutic efficacy in prostate cancer by targeting EZH2 PMID: 40651983

ADC Targets in Oncology

2026-04-10

Ketone drink enhances therapeutic efficacy in prostate cancer by targeting EZH2

Oncogenesis. 2025 Jul 12;14(1):24. doi: 10.1038/s41389-025-00567-0.

Chaehyun Yum ¹ , Richard A Schaefer ¹ , Rui Wang ¹ , Ting-You Wang ¹ , Xiaotong Lu ¹ ² , Qi Liu ¹ , Yanan Ren ¹ , Qingshu Meng ¹ , Yongyong Yang ¹ , Xin Zhang ³ , Yan Xiong ³ , Xufen Yu ³ , Xiaoyu Zhang ⁴ ⁵ ⁶ ⁷ ⁸ , Jian Jin ³ , Xuesen Dong ⁹ ¹⁰ , Yang Yi ¹ ⁴ , Rendong Yang ¹¹ ¹² , Qi Cao ¹³ ¹⁴

Affiliations

1. Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
2. Bioinformatics and Computational Biology Program, University of Minnesota, Minneapolis, MN, USA.
3. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Science, Oncological Science and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
5. Department of Chemistry, Northwestern University, Evanston, IL, USA.
6. Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA.
7. International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA.
8. Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
9. Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.
10. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
11. Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. [email protected].
12. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. [email protected].
13. Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. [email protected].
14. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. [email protected].

Abstract

It is well established that EZH2, a lysine methyltransferase, is upregulated in most aggressive cancers, highlighting the importance of EZH2 in Cancer progression. Recent research has shown that metabolic reprogramming is pivotal in various biological processes, including Cancer. Despite this, evidence of EZH2's role in regulating Cancer metabolism remains limited. Our study reveals a negative correlation between EZH2 and HMGCS2, a gene belonging to the HMG-CoA synthase, in prostate and breast cancers. Interestingly, HMGCS2 is inversely related to Cancer progression and prognosis in these cancers. Furthermore, HMGCS2 is epigenetically repressed by EZH2 both in vitro and in vivo. Notably, restored EZH2 reduces the elevated HMGCS2 levels observed upon EZH2 depletion. Overexpression of HMGCS2 decreases tumorigenesis in both prostate and breast cancers. Additionally, β-hydroxybutyrate (BHB), a downstream metabolite of HMGCS2, impedes prostate Cancer progression by targeting EZH2 via direct protein-compound interaction-mediated protein degradation. More importantly, the ketone drink of BHB administration dramatically reduces tumor size and weight in a therapy-resistant, castration-resistant prostate Cancer patient-derived xenograft model. Combining a ketone drink with FDA-approved drugs enzalutamide and Tazemetostat further suppresses tumor progression. Overall, the EZH2-HMGCS2-BHB regulatory network plays a critical role in the progression of prostate Cancer, and a ketone drink is a novel therapeutic tool for patients with aggressive prostate Cancer.