2. Academic Validation
  3. Diet-metabolism-transcription axis modulates the sensitivity to CDK4/6 inhibitors through RB1 in prostate cancer

Diet-metabolism-transcription axis modulates the sensitivity to CDK4/6 inhibitors through RB1 in prostate cancer

  • Cell Rep. 2025 Nov 25;44(11):116530. doi: 10.1016/j.celrep.2025.116530.
Xurui Li 1,  Zhenghui Sun 1,  Ruijiang Zeng 2,  Ruiling Liu 2,  Pingxia Lin 2,  Zhuo Xing 3,  Xin Jin 4,  Tiejun Yang 5
Affiliations

Affiliations

  • 1 The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
  • 2 Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
  • 3 The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China; Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. Electronic address: [email protected].
  • 4 Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; FuRong Laboratory, Changsha, Hunan 410011, China. Electronic address: [email protected].
  • 5 The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China. Electronic address: [email protected].
PMID: 41196681 DOI: 10.1016/j.celrep.2025.116530
Abstract

A high-fat diet (HFD) promotes tumor progression and therapeutic resistance, but its mechanistic role in prostate Cancer (PCa) remains unclear. In this study, we show that an HFD not only accelerates PCa progression but also significantly reduces sensitivity to CDK4/6 inhibitors. Mechanistically, an HFD activates CDK4, inducing RB1 phosphorylation and facilitating E2F1 release. Meanwhile, phosphorylation of RB1 at the S249/T252 site enhances its interaction with ETS1 and suppresses ETS1's transcriptional activity. Treatment with CDK4/6 inhibitors induces dephosphorylation at this site, relieving ETS1 suppression and promoting PCYT2 expression and phosphatidylcholine metabolic reprogramming. The resulting metabolic products further disrupt RB1-E2F1 binding, leading to additional E2F1 release and increased resistance to CDK4/6 inhibitors. In conclusion, our results identify a diet-metabolism-transcriptional regulatory axis centered on RB1 phosphorylation and ETS1 reactivation, reveal a mechanism of acquired resistance to CDK4/6 inhibitors of castration-resistant PCa, and provide a theoretical basis for combinatorial strategies targeting metabolic and oncogenic signals.

Keywords

CDK4/6 inhibitors; CP: cancer; CP: metabolism; RB1; high-fat diet; prostate cancer.

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