Structural representation of the JAK family members JAK1–3 and TYK2. Shown is the organization of JAKs into the domains JH1–7 and frequent mutations of JAKs in tumor cells.

The diagram shows wild-type JAK-STAT (left) and mutant JAK2^V617F-STAT (right) signaling. The binding of a cytokine, exemplified for erythropoietin (EPO), promotes the dimerization of its receptor and subsequently JAK2 dimerization and crossphosphorylation. Phosphorylation of the cytokine receptor creates a binding interface for the SH2 domains of preformed STAT dimers. These become phosphorylated by JAKs, form high-avidity dimers via SH2-pY interactions, and enter the nucleus to induce specific gene expression patterns. Cognate STAT consensus motifs in gene promoters are usually the palindromic γ-activated sequences and the interferon-stimulated response elements. Independent of receptor activation and due to structurally facilitated JAK2 dimer formation, JAK2^V617F activates STATs. The resulting tonic gene activation promotes tumorigenesis. This article summarizes how HDACi can alter the molecules and mechanisms of these pathways. We exemplarily depict the suppressive effects of HDACi on JAK2^V617F. These rely on the acetylation of STATs and their subsequent dephosphorylation and on the induction of SOCS proteins that directly inhibit and promote the degradation of JAKs. HDACi additionally decrease transcription of the JAK2 gene locus and accelerate the proteasomal degradation of JAK2^V617F; see text for details. Created with biorender.com.

HDACs are dysregulated in cancer and control chromatin remodeling with histone acetyl transferases (HATs). (A) Cancer cells display altered HDAC expression and activity. This creates a vulnerability of transformed cells to HDACi. (B) HATs catalyze the acetylation of lysine moieties of histone and nonhistone proteins using acetyl-CoA as a cosubstrate. The acetyl groups neutralize the positively charged histone tails and thereby weaken the electrostatic interactions between histones and the negatively charged phosphate backbone of DNA. This causes a relaxed state of chromatin. In a chromatin context-dependent manner, this can render DNA more accessible for transcription (depicted as accelerated speed). Elimination of the acetyl groups by HDAC activity reverses these processes. HDACs catalyze the removal of the acetyl group from the lysine residues, causing the release of the acetate molecule. These alterations in transcription critically affect key cellular processes. (C) Biochemistry of the acetylation/deacetylation reactions. Created with BioRender.com.

HDAC classes, HDACi, and mode of action. (A) Schematic representation of different classes of HDACs and their pharmacological inhibitors. (B) Targeting the Zn²⁺-dependent HDACs by HDACi. The structure of hydroxamic acids is shown as an example of the three typical parts of an HDACi. The cap group binds the HDAC at its rim, and the linker serves to position the Zn²⁺-binding part toward the coordinated metal in the catalytic cleft of the HDAC. (C) The double-hit approach uses JAK-HDAC dual inhibitors. The cap group provides possibilities to attach a TKi. The TKi must preserve its structures that compete with ATP and the HDACi must retain the Zn²⁺-binding moiety. Ac-K, acetylated lysine residue in a protein.