2. Academic Validation
  3. The noncanonical function of liver-type phosphofructokinase potentiates the efficacy of HDAC inhibitors in cancer

The noncanonical function of liver-type phosphofructokinase potentiates the efficacy of HDAC inhibitors in cancer

  • Signal Transduct Target Ther. 2025 Oct 14;10(1):341. doi: 10.1038/s41392-025-02443-0.
Taiyu Shang # 1 2,  Tianyi Jiang # 3 4,  Jiangqi Tan 2,  Haolin Jiang 2,  Mengyou Xu 2,  Yufei Pan 2 5,  Yunkai Lin 2 5,  Xiaowen Cui 6,  Chenxi Tian 2,  Huibo Feng 2,  Yibin Chen 2,  Mengmiao Pei 7,  Xin Geng 2,  Shuqun Cheng 7,  Yexiong Tan 2 5,  Hongyang Wang 8 9 10 11 12,  Liwei Dong 13 14
Affiliations

Affiliations

  • 1 Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 2 National Center for Liver Cancer, Naval Medical University, Shanghai, China.
  • 3 National Center for Liver Cancer, Naval Medical University, Shanghai, China. jiangtianyi@smmu.edu.cn.
  • 4 International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China. jiangtianyi@smmu.edu.cn.
  • 5 International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
  • 6 Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
  • 7 Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
  • 8 Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. hywangk@vip.sina.com.
  • 9 National Center for Liver Cancer, Naval Medical University, Shanghai, China. hywangk@vip.sina.com.
  • 10 International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China. hywangk@vip.sina.com.
  • 11 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. hywangk@vip.sina.com.
  • 12 Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, China. hywangk@vip.sina.com.
  • 13 National Center for Liver Cancer, Naval Medical University, Shanghai, China. dlw@smmu.edu.cn.
  • 14 International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China. dlw@smmu.edu.cn.
  • # Contributed equally.
PMID: 41083431 DOI: 10.1038/s41392-025-02443-0
Abstract

Zinc-dependent histone deacetylases (HDACs) are pivotal Enzymes governing the epigenetic modulation of gene expression through chromatin remodeling. The dysregulated expression of HDACs is intricately linked to various pathological conditions, including Cancer and inflammation. Histone deacetylase inhibitors (HDACi) have shown therapeutic potential in certain hematologic malignancies. However, the clinical performance of HDACi in solid tumors remains unsatisfactory, and the precise mechanisms of its therapeutic effect in solid tumors has not been fully elucidated. In this study, we identified nucleus-localized PFKL (Liver-type phosphofructokinase), as a key regulator of HDACi efficacy and intracellular epigenetic dynamics. Nuclear PFKL directly binds to class I HDACs through interacting with zinc-binding sites, thereby inhibiting HDAC enzymatic activity and promoting intracellular histone acetylation. In addition, the Thr562 residue within PFKL enhances the chelation effect between the zinc-binding group (ZBG) of the HDACi romidepsin and the zinc within the HDACs, further promoting drug efficacy. Based on the mechanism of PFKL facilitates the efficacy of romidepsin, we developed a therapeutic peptide, PFKL-552-572-R8, which significantly enhances the antitumor effect of romidepsin both in vitro and in vivo. Our findings reveal that spatiotemporal regulation confers a moonlight function to PFKL as an endogenous HDAC Inhibitor to maintain the stability of epigenetic modifications and highlight PFKL as a promising therapeutic target for enhancing the clinical utility of HDACi in solid tumors.

Figures
Products