Journal Article

HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis

Liu, Qiaojie, Zhang, Baokai, Li, Xiangyue, Wu, Han, Xiang, Zou, Zhang, Zhijiang, Yin, Yue, Zhang, Fang, Yang, Dan, Wang, Hongyan, Feng, Qiuyun, Li, Weiyun, Zhou, Xi, Qi, Linlin, Peng, Chao, Wei, Bin, Tang, Zhao-Hui, Liu, Chang

2021

Overview

Although inflammation is critical for the clearance of pathogens, uncontrolled inflammation also contributes to the development of multiple diseases such as cancer and sepsis. Since NF-κB–mediated transactivation in the nucleus is pivotal downstream of various stimuli to induce inflammation, searching the nuclear-localized targets specifically regulating NF-κB activation will provide important therapeutic application. Here, we have identified that homeodomain-interacting protein kinase 2 (HIPK2), a nuclear serine/threonine kinase, increases its expression in inflammatory macrophages. Importantly, HIPK2 deficiency or overexpression could enhance or inhibit inflammatory responses in LPS-stimulated macrophages, respectively. HIPK2-deficient mice were more susceptible to LPS-induced endotoxemia and CLP-induced sepsis. Adoptive transfer of Hipk2 +/− bone marrow cells (BMs) also aggravated AOM/DSS-induced colorectal cancer. Mechanistically, HIPK2 bound and phosphorylated histone deacetylase 3 (HDAC3) at serine 374 to inhibit its enzymatic activity, thus reducing the deacetylation of p65 at lysine 218 to suppress NF-κB activation. Notably, the HDAC3 inhibitors protected wild-type or Hipk2−/− BMs-reconstituted mice from LPS-induced endotoxemia. Our findings suggest that the HIPK2-HDAC3-p65 module in macrophages restrains excessive inflammation, which may represent a new layer of therapeutic mechanism for colitis-associated colorectal cancer and sepsis.

• Publisher: National Academy of Sciences
• Subject: Acetylation / Adoptive transfer / Animals / Biological Sciences / Bone marrow / Cancer / Cecum - pathology / Colitis / Colitis - complications / Colorectal cancer / Colorectal Neoplasms - etiology / Colorectal Neoplasms - metabolism / Cytokines - biosynthesis / Deacetylation / Endotoxemia / Endotoxemia - complications / Enzymatic activity / HIPK2 protein / Histone deacetylase / Histone Deacetylase Inhibitors - pharmacology / Histone Deacetylases - metabolism / Homeobox / Humans / Immunology and Inflammation / Inflammation / Inflammation - pathology / Inflammation Mediators - metabolism / Inflammatory bowel disease / Kinases / Ligation / Lipopolysaccharides / Lysine / Lysine - metabolism / Macrophages / Macrophages - metabolism / Macrophages - pathology / Mice / NF-kappa B - metabolism / NF-κB protein / Phosphorylation - drug effects / Phosphoserine - metabolism / Protein Serine-Threonine Kinases - metabolism / Protein-serine/threonine kinase / Punctures / Sepsis / Sepsis - etiology / Sepsis - metabolism / Toll-Like Receptor 4 - metabolism / Toll-Like Receptor 9 - metabolism / Transcription Factor RelA - metabolism / Up-Regulation