Acidosis and Hypoxic Tumor Microenvironment Induces Changes to Histones Acetylation and Methylation in Oral Squamous Cell Carcinoma.

Hypoxia and acidosis are ubiquitous hallmarks of the tumor microenvironment (TME), and in most solid cancers they have been linked to rewired cancer cell metabolism. These TME stresses are linked to changes in histone post-translational modifications (PTMs) like methylation and acetylation, which lead to tumorigenesis and drug resistance. Hypoxia and acidosis TME cause changes in histone PTMs by impacting the activities of histone-modifying enzymes. These alterations are yet to be extensively explored in oral squamous cell carcinoma (OSCC), one of the most prevalent cancers in developing countries. Hypoxia, acidosis, or hypoxia with acidosis TME affecting histone acetylation and methylation in the CAL27 OSCC cell line was studied using liquid chromatography-mass spectrometry (LC-MS)-based proteomics. The study identified several well-known histone marks, in the context of their functionality in gene regulation, such as H2AK9Ac, H3K36me3, and H4K16Ac. The results provide insights into the histone acetylation and methylation associated with hypoxia and acidosis TME, causing changes in their level in a position-dependent manner in the OSCC cell line. Hypoxia and acidosis, separately and in combination, cause differential impacts on histone methylation and acetylation in OSCC. The work will help uncover tumor cell adaptation to these stress stimuli in connection to histone crosstalk events.