TY - JOUR T1 - <strong>Pharmacological Modulation of the Crosstalk between Aberrant Janus Kinase Signaling and Epigenetic Modifiers of the Histone Deacetylase Family to Treat Cancer</strong> JF - Pharmacological Reviews JO - Pharmacol Rev DO - 10.1124/pharmrev.122.000612 SP - PHARMREV-AR-2022-000612 AU - Al-Hassan M. Mustafa AU - Oliver H. Krämer Y1 - 2022/01/01 UR - http://pharmrev.aspetjournals.org/content/early/2022/12/08/pharmrev.122.000612.abstract N2 - Janus kinase (JAK) signaling is frequently hyperactivated in human cancers and therefore an appreciated drug target. Numerous mutant JAK molecules as well as inherent and acquired drug resistance mechanisms limit the efficacy of JAK inhibitors (JAKi). There is accumulating evidence that epigenetic mechanisms control JAK-dependent signaling cascades. Like JAKs, epigenetic modifiers of the histone deacetylase (HDAC) family regulate the growth and development of cells and are often dysregulated in cancer cells. The notion that inhibitors of histone deacetylases (HDACi) abrogate oncogenic JAK-dependent signaling cascades illustrates an intricate crosstalk between JAKs and HDACs. Here, we summarize how structurally divergent, broad-acting as well as isoenzyme-specific HDACi, hybrid fusion pharmacophores containing JAKi and HDACi, and PROTACs for JAKs inactivate the four JAK proteins JAK1, JAK2, JAK3, and TYK2. These agents suppress aberrant JAK activity through specific transcription-dependent processes and mechanisms that alter the phosphorylation and stability of JAKs. Pharmacological inhibition of HDACs abrogates allosteric activation of JAKs, overcomes limitations of ATP-competitive type 1 and type 2 JAKi, and interacts favorably with JAKi. Since such findings were collected in cultured cells, experimental animals, and cancer patients, we condense pre-clinical and translational relevance. We also discuss how future research on acetylation-dependent mechanisms that regulate JAKs might allow the rational design of improved treatments for cancer patients. Significance Statement Reversible lysine-ɛ-N acetylation and deacetylation cycles control phosphorylation-dependent JAK-STAT signaling. The intricate crosstalk between these fundamental molecular mechanisms provides opportunities for pharmacological intervention strategies with modern small molecule inhibitors. This could help patients suffering from cancer. ER -