PFKL is an Epigenetic Factor that Enhances HDACi Activity in Solid Tumors

Histone deacetylase inhibitors (HDACi), successfully implemented against hematologic cancers, are of limited clinical utility in solid tumors. This is likely due to a multitude of reasons that include intrinsic resistance, tumor heterogeneity, and poor pharmacokinetic profiles. However, the specific molecular mechanisms underlying HDACi efficacy, or lack thereof, in solid malignancies remain obscure.

An exciting new study in Signal Transduction and Targeted Therapy by Shang et al. reveals a novel epigenetic mechanism linking liver-type phosphofructokinase (PFKL) to HDACi responsiveness (1). Beginning with their discovery that certain HDACi agents showed activity against cholangiocarcinoma cells, the authors employed genome-wide CRISPR screening to identify cellular factors involved in this response. The authors found that PFKL is a key determinant of HDACi sensitivity, with its loss inducing resistance to the HDACi romidepsin while high PFKL expression enhanced sensitivity.

Mechanistically, they determined that nuclear PFKL binds class I HDACs at zinc-binding motifs, suppressing HDAC activity and promoting histone acetylation through an epigenetic action not involving PFKL’s glycolytic enzymatic function. Structural modeling and molecular dynamics simulations revealed that Thr562 of PFKL enhances the chelation between romidepsin’s zinc-binding group and the HDAC catalytic zinc, stabilizing the ternary complex. A PFKL-derived peptide (PFKL-552-572-R8) mimicking this interaction significantly enhanced romidepsin efficacy, establishing PFKL as a moonlighting epigenetic regulator and biomarker for overcoming HDACi resistance in solid tumors.