title: AAG8 promotes carcinogenesis by activating STAT3.
abstract: Dysregulation of signalling pathways by changes of gene expression contributes to hallmarks of cancer. The ubiquitously expressed chaperone protein AAG8 (aging-associated gene 8 protein, encoded by the SIGMAR1 gene) is often found to be overexpressed in various cancers. AAG8 is involved in ER (endoplasmic reticulum)-associated degradation and has been intensively elaborated in neuroscience. However, its rationale in carcinogenesis has rarely been noticed. In this study, we explored the intrinsic oncogenetic roles of AAG8 in cancer cells and found that AAG8 promoted carcinogenesis both in vitro and in vivo. We further characterized AAG8, for the first time to our knowledge, as a STAT3 activator and elucidated that it alternatively activated STAT3 in addition to IL6/JAK pathway. Based on these findings and a drug screening study, we demonstrated that combined inhibition of AAG8 and IL6/JAK signalling synergistically limits cancer cell growth. Taken together, our findings shed light on the fundamental evidences for identification of AAG8 as an oncoprotein and potential target for cancer prevention, as well as highlight the importance of ER proteins in contributing to JAK/STAT signaling and carcinogenesis.
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Bing
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kawahara
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Ehata
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan; Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. Electronic address: nagamune@bio.t.u-tokyo.ac.jp.
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Nagamune
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009570:Nitriles; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines; D034622:RNA Interference; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D000097605:Sigma-1 Receptor
chemical_list: D015850:Interleukin-6; D053612:Janus Kinases; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D017480:Receptors, sigma; D050796:STAT3 Transcription Factor; D000097605:Sigma-1 Receptor; C540383:ruxolitinib
keywords: AAG8; Cancer; STAT3