title: Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity.
abstract: Tumor suppressor genes are frequently silenced in cancer cells by enzymes catalyzing epigenetic histone modifications. The peptidylarginine deiminase family member PAD4 (also called PADI4) is markedly overexpressed in a majority of human cancers, suggesting that PAD4 is a putative target for cancer treatment. Here, we have generated novel PAD inhibitors with low micromolar IC(50) in PAD activity and cancer cell growth inhibition. The lead compound YW3-56 alters the expression of genes controlling the cell cycle and cell death, including SESN2 that encodes an upstream inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Guided by the gene expression profile analyses with YW3-56, we found that PAD4 functions as a corepressor of p53 to regulate SESN2 expression by histone citrullination in cancer cells. Consistent with the mTORC1 inhibition by SESN2, the phosphorylation of its substrates including p70S6 kinase (p70S6K) and 4E-BP1 was decreased. Furthermore, macroautophagy is perturbed after YW3-56 treatment in cancer cells. In a mouse xenograft model, YW3-56 demonstrates cancer growth inhibition activity with little if any detectable adverse effect to vital organs, whereas a combination of PAD4 and histone deacetylase inhibitors further decreases tumor growth. Taken together, our work found that PAD4 regulates the mTORC1 signaling pathway and that PAD inhibitors are potential anticancer reagents that activate tumor suppressor gene expression alone or in combination with histone deacetylase inhibitors.
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Wang
authors.forename: Pingxin
authors.initials: P
authors.lastname: Li
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.forename: Xiangyun Amy
authors.initials: XA
authors.lastname: Chen
authors.forename: Jianhui
authors.initials: J
authors.lastname: Wu
authors.forename: Megan
authors.initials: M
authors.lastname: Fisher
authors.forename: Kira
authors.initials: K
authors.lastname: Oshaben
authors.forename: Na
authors.initials: N
authors.lastname: Zhao
authors.forename: Ying
authors.initials: Y
authors.lastname: Gu
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.forename: Yanming
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D011506:Proteins / Q000378:metabolism*; D012509:Sarcoma / Q000188:drug therapy / Q000473:pathology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D015533:Transcriptional Activation / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000084622:Sestrins
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006867:Hydrolases; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D011506:Proteins; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C465398:SESN2 protein, human; D000084622:Sestrins; C495901:TP53 protein, human; C000629235:PADI4 protein, human; C552151:peptidylarginine deiminase 4, mouse