Li Zongwei, Zhuang Ming, Zhang Lichao, Zheng Xingnan, Yang Peng, Li Zhuoyu
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.
Sci Rep. 2016 Jul 27;6:30406. doi: 10.1038/srep30406.
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.
高葡萄糖调节蛋白78（GRP78）的表达有助于多种癌症表型特征的获得，GRP78的多效致癌功能可能源于其不同的亚细胞分布。有趣的是，据报道GRP78可从实体瘤细胞中分泌出来，参与肿瘤微环境中的细胞间通讯。然而，这种分泌的潜在机制仍然不清楚。在这里，我们报告GRP78通过外泌体从结肠癌细胞中分泌。组蛋白去乙酰化酶（HDAC）抑制剂通过诱导GRP78在内质网中聚集来阻断其释放。从机制上讲，HDAC抑制剂处理抑制了HDAC6的活性并导致GRP78乙酰化增加；乙酰化的GRP78随后与III类磷酸肌醇-3激酶VPS34结合，从而阻止GRP78分选到多囊泡体（MVB）中。值得注意的是，我们发现将HDAC6的去乙酰化位点之一第633位的赖氨酸替换为谷氨酰胺来模拟GRP78乙酰化，会导致GRP78分泌减少并损害体外肿瘤细胞生长。因此，我们的研究揭示了一种迄今为止未知的GRP78分泌机制，也可能为HDAC抑制剂的治疗应用提供启示。
