Abstract 597: CREBBP mutation promotes tumor growth by impairing HDAC3 acetylation-dependent expression of PTEN.

Abstract Somatic mutations in CREB binding protein (CREBBP or CBP), which encodes a histone acetyltransferase, are frequently observed in cancers such as lymphoma and non-small cell lung cancer. Here, we report that CREBBP loss-of-function (LOF) mutations lead to the deacetylation of histone deacetylase 3 (HDAC3) and promote cancer cell growth by transcriptional silencing of the tumor suppressor gene phosphatase and tensin homolog (PTEN). Mechanistically, we found that CBP specifically binds to HDAC3 and acetylates it at a previously unknown residue, which is necessary for reducing HDAC3 activity and increasing histone acetylation. Additionally, our data show that HDAC3 acetylation is crucial for maintaining PTEN expression via acetylated histone-regulated transcription. The loss of HDAC3 acetylation in cancers with CBP LOF mutations results in PTEN deficiency, thereby promoting tumor development and resistance to chemotherapy. Our findings reveal a novel epigenetic mechanism regulating PTEN expression and suggest that HDAC3 could be a potential alternative target for cancers with CBP LOF mutations.To our knowledge, this is the first report of the previously unrecognized acetylation of HDAC3, a critical deacetylase involved in cancer. This discovery is significant because our data show that HDAC3 acetylation is essential for regulating its activity by disrupting the CK2a-mediated phosphorylation of HDAC3. We clarify that HDAC3 acetylation is controlled by the acetyltransferase CBP and the deacetylase Sirt1. The key finding is the connection between HDAC3 acetylation and PTEN loss in CBP mutant cancers. Our data also link HDAC3 acetylation to cancer patient survival and suggest that targeting HDAC3 could help restore the tumor suppressor PTEN in cancers with CBP LOF mutations. Our results provide a new understanding of the epigenetic regulation of PTEN in tumor development. Citation Format: Xiang Wang, Wenquan Hu, Qing Robert Miao. CREBBP mutation promotes tumor growth by impairing HDAC3 acetylation-dependent expression of PTEN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 597.