title: Acetylation modification regulates GRP78 secretion in colon cancer cells.
abstract: High glucose-regulated protein 78 (GRP78) expression contributes to the acquisition of a wide range of phenotypic cancer hallmarks, and the pleiotropic oncogenic functions of GRP78 may result from its diverse subcellular distribution. Interestingly, GRP78 has been reported to be secreted from solid tumour cells, participating in cell-cell communication in the tumour microenvironment. However, the mechanism underlying this secretion remains elusive. Here, we report that GRP78 is secreted from colon cancer cells via exosomes. Histone deacetylase (HDAC) inhibitors blocked GRP78 release by inducing its aggregation in the ER. Mechanistically, HDAC inhibitor treatment suppressed HDAC6 activity and led to increased GRP78 acetylation; acetylated GRP78 then bound to VPS34, a class III phosphoinositide-3 kinase, consequently preventing the sorting of GRP78 into multivesicular bodies (MVBs). Of note, we found that mimicking GRP78 acetylation by substituting the lysine at residue 633, one of the deacetylated sites of HDAC6, with a glutamine resulted in decreased GRP78 secretion and impaired tumour cell growth in vitro. Our study thus reveals a hitherto-unknown mechanism of GRP78 secretion and may also provide implications for the therapeutic use of HDAC inhibitors.
authors.affiliation: Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, 030006, China.|Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: General Surgical Department, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhuang
authors.affiliation: Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, 030006, China.
authors.forename: Lichao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
authors.forename: Xingnan
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, 030006, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.affiliation: Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, 030006, China.
authors.forename: Zhuoyu
authors.initials: Z
authors.lastname: Li
mesh_terms: D000107:Acetylation; D000818:Animals; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006360:Heat-Shock Proteins / Q000378:metabolism*; D000073864:Histone Deacetylase 6 / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011485:Protein Binding; D011499:Protein Processing, Post-Translational
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; C000717248:Hspa5 protein, mouse; D058546:Class III Phosphatidylinositol 3-Kinases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6