HIPK2 phosphorylates HDAC3 for NF-[kappa]B acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis.

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Date: July 13, 2021
Publisher: National Academy of Sciences
Document Type: Report
Length: 8,659 words
Lexile Measure: 1460L

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Abstract :

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-[kappa]B--mediated transactivation in the nucleus is pivotal downstream of various stimuli to induce inflammation, searching the nuclear-localized targets specifically regulating NF-[kappa]B 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.sup.+/-] 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-[kappa]B activation. Notably, the HDAC3 inhibitors protected wild-type or [Hipk2.sup.-/-] 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. cytokine storm | colon cancer | HIPK2 | HDAC3 phosphorylation | p65 acetylation

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Gale Document Number: GALE|A669890773