Deacetylase HDAC3 needs acetylation to regulate tumor suppressor PTEN expression in non-small cell lung cancer

Phosphates and tensin homolog (PTEN) is a critical tumor suppressor, and even partial reduction of PTEN levels increases cancer susceptibility. PTEN loss frequently occurs in non-small cell lung carcinoma (NSCLC) and is associated with poor diagnosis. However, there are no effective interventions available to prevent or restore PTEN loss. CREB binding protein (CREBBP or CBP) is a well-known acetyltransferase. PTEN loss in lung cancer carrying CBP loss-of-function (LOF) mutations has not been addressed. Here, we showed that the decreased acetylation of histone deacetylase 3 (HDAC3) due to CBP LOF mutations contributes to PTEN loss in lung cancer. HDAC3 is a member of the class I histone deacetylase family. We found HDAC3 itself is acetylated by CBP at a previously unknown acetylation residue. Our data demonstrated that HDAC3 acetylation is required for gearing down HDAC3 activity and increasing the acetylation of histone proteins to promote the transcription of PTEN. Our findings suggest that HDAC3 acetylation is required for preserving the PTEN expression. The impaired HDAC3 acetylation in CBP LOF mutation lung cancer leads to PTEN loss and consequently promotes tumorigenesis and tumor resistance to chemotherapy. Our findings reveal epigenetic mechanisms of regulating PTEN expression and indicate HDAC3 is a potential target for restoring the tumor suppressor PTEN in CBP LOF mutation cancer.