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

Abstract

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.