胰腺癌发展中，细胞如何耐受营养缺失微环境的分子机制并不清楚。延胡索酸水合酶（FH）是重要抑癌基因，在多种肿瘤中存在功能缺失突变。已报导FH可区域调节组蛋白甲基化，而FH能否因此介导基因转录调控仍不明了。转录因子ATF2介导的信号通路在细胞凋亡过程中有重要作用。我们前期研究表明：胰腺导管细胞外环境葡萄糖缺失可通过代谢应激激酶AMPK促进FH与ATF2结合，并将FH招募到ATF2下游基因启动子区域进而影响区域组蛋白甲基化。而胰腺导管癌细胞中O-糖基化转移酶（OGT）可抑制葡萄糖缺失诱导的FH与ATF2结合。本课题旨在证明AMPK-FH-ATF2-H3信号通路通过FH在ATF2下游基因启动子区域的局部代谢功能影响组蛋白甲基化并调控ATF2下游基因转录从而介导营养微环境对细胞存活的调控；胰腺癌细胞可能通过O-糖基化FH抑制这一信号通路从而耐受营养缺失微环境，促进胰腺癌的发生发展。

During pancreatic tumorigenesis, the mechanism for cells surviving from limited nutrient microenvironment is not clear. Fumarate hydratase (FH) is a critical cancer suppressor gene, and its inactive mutations are frequently detected in multiple tumors. The previous report shows, as a metabolic enzyme, FH mediates Histone methylation through its metabolic product fumarate. As Histone methylation involving in transcriptional regulation, whether FH could mediate gene transcription through affecting Histone methylation remains unknown. Activating transcription factor 2 (ATF2) play an important role in the process of cancer cell apoptosis. In our preliminary studies, we found under glucose deprivation condition, AMPK phosphorylated FH and promoted the interaction between FH and ATF2. Then, FH was recruited at the promoter region of ATF2 targeted genes and further affected local Histone methylation （H3K36Me2） level. Moreover, this pathway was inactivated in pancreatic duct cancer cells through protein O-glycosylation, which could be reversed by O-glycosylation enzyme OGT (β-N-acetylg-lucosaminyl transferase) knockdown. Collectively, in this project, we expect to prove the AMPK-FH-ATF2-H3 signaling pathway may transcriptional regulate ATF2 targeted genes and contribute to the determination of cell fate by nutrient microenvironment through local regulation of H3 methylation, and the negative regulation of this pathway by FH glycosylation may play a key role for pancreatic cancer cells surviving from limited nutrient microenvironment and pancreatic tumorigenesis.