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

TL;DR

This study shows that a protein called PFKL boosts the effectiveness of HDAC inhibitors in cancer by regulating epigenetic processes.

Contribution

The study reveals a new noncanonical role of PFKL in enhancing HDAC inhibitor efficacy through direct interaction and zinc chelation.

Findings

Nuclear PFKL inhibits HDAC activity by binding to zinc-binding sites.

The Thr562 residue in PFKL enhances the drug romidepsin's chelation with HDACs.

A PFKL-derived peptide significantly improves romidepsin's antitumor effects in models.

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.

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