Somatic Hdac4-902fs mutations lead to loss of HDAC4 function through nonsense-mediated mRNA degradation

Histone deacetylases (HDACs) are essential chromatin regulators and are involved in the regulation of gene expression by removing acetyl groups from histone and non-histone proteins. Histone deacetylase 4 (HDAC4) is known to regulate the process of endochondral ossification in mice by non-enzymatic repression of the activity of the RUNX2 transcription factor (TF) and to control cardiac metabolism in physiological stress situations. In this study, we examined the function of somatic HDAC4-902 frameshift (fs) mutations that are frequently observed in gastric and colon adenocarcinoma patients. Whether these mutations lead to a gain- or a loss-of-function is currently unknown. Here we generated a murine model bearing a germline HDAC4-methionine (M) amino acid (AA) 902-to-histidine (H) frameshift (M902Hfs) mutation. HDAC4-M902Hfs mice phenocopied HDAC4 null mice and present with premature ossification and early postnatal death. Mechanistically, we found that the HDAC4-M902Hfs mutation induced nonsense-mediated mRNA decay, resulting in loss of HDAC4 protein. This loss-of-function (LOF) effect was further supported by increased mRNA and protein expression of runt-related transcription factor-2 (RUNX2) and reduced class IIa HDAC enzymatic activity, indicating that HDAC4 contributes significantly to endogenous class IIa HDAC activity. Patient-derived data suggest that the HDAC4-902fs mutation is associated with reduced mRNA expression of HDAC4. In conclusion, our study identify that HDAC4-902fs mutation is a loss-of-function mutation, but raises the new question whether the loss of non-enzymatic mechanisms or the reduction in class IIa HDAC activity contributes to tumor progression.