PX-12 modulates vorinostat-induced acetylation and methylation marks in CAL 27 cells

The hypoxic tumor microenvironment (TME) in oral squamous cell carcinoma (OSCC) is primarily regulated by hypoxia-inducible factor-1 alpha (HIF-1α), impacting histone acetylation and methylation, which contribute to drug resistance. Vorinostat, a histone deacetylase inhibitor (HDACi), de-stabilizes HIF-1α, while PX-12, a thioredoxin-1 (Trx-1) inhibitor, prevents HIF-1α accumulation. Combining HDACi with a Trx-1 inhibitor may enhance efficacy and reduce resistance by increasing reactive oxygen species (ROS) in cancer cells. This study examines how PX-12 influences vorinostat-induced histone modifications under hypoxia in the OSCC cell line CAL 27 using mass spectrometry. The OSCC cell line CAL 27 was used to assess histone post-translational modifications induced by PX-12 and Vorinostat under hypoxic conditions through mass spectrometry. The proteomic analysis (ProteomeXchange identifier PXD053244) revealed several crucial histone marks, such as H3K4me1, H3K9ac, H3K9me, H3K14ac, H3K27me, H3K36me, H4K12Ac, and H4K16ac. Along with site-specific histone modifications, exposure of cells to vorinostat and PX-12 alone or in combination affects the global acetylation and methylation levels under hypoxia. Mass spectrometry-based proteomics highlighted the impact of vorinostat and PX-12 on histone acetylation and methylation, offering valuable insights into the epigenetic mechanisms in OSCC and paving a way for epigenetic-based oral cancer therapeutics.