Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, P. R. China.
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.
Hepatology. 2017 Aug;66(2):631-645. doi: 10.1002/hep.29202. Epub 2017 Jun 19.
Up-regulated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is observed in multiple cancers with unclear mechanism. Using GAPDH transgenic mouse and a mouse model of diethylnitrosamine-induced hepatocellular carcinoma (HCC), here we show that GAPDH overexpression aggravated tumor development by activating cell proliferation and inflammation. In cultured hepatic cells, overexpression of GAPDH or a catalytic domain-deleted GAPDH (GAPDH ) affected metabolism, up-regulated phosphoglycerate dehydrogenase (PHGDH), increased histone methylation levels, and promoted proliferation. Consistently, inhibition of GAPDH by short hairpin RNA reprogrammed metabolism down-regulated PHGDH and histone methylation, and inhibited proliferation. The xenograft study suggested that HepG2 cells overexpressing GAPDH or GAPDH similarly promoted tumor development, whereas knockdown PHGDH in GAPDH overexpressing cells significantly inhibited tumor development. In liver sections of HCC patients, increased GAPDH staining was found to be positively correlated with PHGDH and histone methylation staining.
GAPDH increases histone methylation levels by up-regulating PHGDH, promoting diversion from glycolysis to serine biosynthesis, and consequently accelerating HCC development. (Hepatology 2017;66:631-645).
在多种癌症中观察到甘油醛-3-磷酸脱氢酶（GAPDH）上调，但机制尚不清楚。本研究使用 GAPDH 转基因小鼠和二乙基亚硝胺诱导的肝癌（HCC）小鼠模型，结果表明 GAPDH 过表达通过激活细胞增殖和炎症加剧肿瘤发展。在培养的肝细胞中，GAPDH 过表达或缺失催化结构域的 GAPDH（GAPDH ）影响代谢，上调磷酸甘油酸脱氢酶（PHGDH），增加组蛋白甲基化水平，并促进增殖。一致地，短发夹 RNA 抑制 GAPDH 重编程代谢，下调 PHGDH 和组蛋白甲基化，并抑制增殖。异种移植研究表明，过表达 GAPDH 或 GAPDH 的 HepG2 细胞同样促进肿瘤发展，而在过表达 GAPDH 的细胞中敲低 PHGDH 则显著抑制肿瘤发展。在 HCC 患者的肝组织切片中，发现 GAPDH 染色增加与 PHGDH 和组蛋白甲基化染色呈正相关。
GAPDH 通过上调 PHGDH 增加组蛋白甲基化水平，促进糖酵解向丝氨酸生物合成的转变，从而加速 HCC 的发展。（《肝脏病学》2017；66:631-645）。
