Metabolic modulation of histone acetylation mediated by HMGCL activates the FOXM1/β-catenin pathway in glioblastoma

Neuro Oncol. 2024 Apr 5;26(4):653-669. doi: 10.1093/neuonc/noad232.


Background: Altered branched-chain amino acid (BCAA) metabolism modulates epigenetic modification, such as H3K27ac in cancer, thus providing a link between metabolic reprogramming and epigenetic change, which are prominent hallmarks of glioblastoma multiforme (GBM). Here, we identified mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase (HMGCL), an enzyme involved in leucine degradation, promoting GBM progression and glioma stem cell (GSC) maintenance.

Methods: In silico analysis was performed to identify specific molecules involved in multiple processes. Glioblastoma multiforme cells were infected with knockdown/overexpression lentiviral constructs of HMGCL to assess malignant performance in vitro and in an orthotopic xenograft model. RNA sequencing was used to identify potential downstream molecular targets.

Results: HMGCL, as a gene, increased in GBM and was associated with poor survival in patients. Knockdown of HMGCL suppressed proliferation and invasion in vitro and in vivo. Acetyl-CoA was decreased with HMGCL knockdown, which led to reduced NFAT1 nuclear accumulation and H3K27ac level. RNA sequencing-based transcriptomic profiling revealed FOXM1 as a candidate downstream target, and HMGCL-mediated H3K27ac modification in the FOXM1 promoter induced transcription of the gene. Loss of FOXM1 protein with HMGCL knockdown led to decreased nuclear translocation and thus activity of β-catenin, a known oncogene. Finally, JIB-04, a small molecule confirmed to bind to HMGCL, suppressed GBM tumorigenesis in vitro and in vivo.

Conclusions: Changes in acetyl-CoA levels induced by HMGCL altered H3K27ac modification, which triggers transcription of FOXM1 and β-catenin nuclear translocation. Targeting HMGCL by JIB-04 inhibited tumor growth, indicating that mediators of BCAA metabolism may serve as molecular targets for effective GBM treatment.

Keywords: FOXM1; HMGCL; glioblastoma; histone acetylation; metabolic regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl Coenzyme A / genetics
  • Acetyl Coenzyme A / metabolism
  • Acetylation
  • Aminopyridines*
  • Cell Line, Tumor
  • Cell Proliferation
  • Forkhead Box Protein M1 / genetics
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma* / pathology
  • Histones / genetics
  • Humans
  • Hydrazones*
  • Lyases* / genetics
  • Lyases* / metabolism
  • beta Catenin / genetics


  • Acetyl Coenzyme A
  • Aminopyridines
  • beta Catenin
  • Forkhead Box Protein M1
  • FOXM1 protein, human
  • Histones
  • Hydrazones
  • JIB-04
  • Lyases
  • CTNNB1 protein, human
  • 3-hydroxy-3-methylglutaryl-coenzyme A lyase