Jiang Yuhui, from the affiliated First People's Hospital, first revealed the new mechanism of gene tranion regulated by fumaric hydratase

Chromatin-associated fumarase (fumarate hydratase/FH) affects histone methylationvia its metabolic activity. However, it is unclear how this processis involved in gene tranion. A few days ago, Researcher Jiang Yuhui and his group, from the affiliated First People‘s Hospital, published an article in Nature Cell Biology magazine online (IF=20.06) titledO - GlcNAcylation of fumarase maintains tumour growth under glucose deficiency of the research paper, which reveals the mechanism howfumaric hydratase regulates gene tranion. In addition, sinceit still remains to be clarified how the high expression of β-N-acetylglucosaminyl transferase(O-GlcNA transeferase/OGT) in pancreatic cancer affects the growth of tumor, this study has shown the linkage betweenabnormal OGT activity and growth advantageof cancer cells under glucose deficiency, uncovering an underlying tranion regulation by FH O-GlcNacylation.

FH is a key enzyme involved in the tricarboxylic acid cycle, which can catalyze the transformation of fumarate into L-malate. It has been reported that FH is related to the occurrence of various tumors. FH functional mutated inactivation can be detected in a variety of cancer tissues and promote the occurrence of tumors.

Some metabolic enzymes have other non-metabolic functions in addition to their classical metabolic functions. During his postdoctoral stay in Anderson Cancer Center in the United States (MD Anderson Cancer Center), researcher Jiang Yuhui has found that FH can affect histone methylation through its metabolites fumarate which is an antagonistofα-KG dependent demethylase, which promotes the DNA repair. It is well known that histone methylation plays a key role in tranion which is one of cell basic biological activities. However, whether FH can regulate the gene tranion through the fumarate and then influence histone methylation has not been studied and reported.

In addition, some studies have shown that metabolic enzymeshave other non-metabolic functions in the presence of external stimuli except performing their classic metabolic functions.

In the study, Professor Jiang Yuhui and his group firstly found that, in normal pancreatic ductal epithelial cells, glucose deficiency promoted the combination of FH and tranion factors ATF2 (ATF2 is identificated by mass spectrometry). Then further study showed that when glucose wasdeficient (AMPK can be activated under glucose deficiency or energy shortage), the FH-Ser75 was phosphorylatedmediated by AMPK, which was recruited to ATF2 downstream gene promoter regions as the interaction of ATF2.And the locally produced FH can inhibit the effect of lysine demethylase KDM2A on histone methylation in promoter region, thus promoting gene expression of cell cycle block. In addition, the researchers also found that the FH-Ser75 could also be modified by O-GlcNAcylation, which could block the interaction between FH and ATF2 and downstream signaling pathways. The pancreatic cancer cells with high expression of OGT can still maintain high FH glycosylation and then suppress cell cycle arrestcaused by FH - ATF2 signaling pathways under glucose deficiency, at last maintain tumor cell growth.

It is also significant that in the specimensof pancreatic cancer patients, the FH-Ser75 phosphorylation level inversely correlates with the OGT level and poor prognosis in pancreatic cancer patients. Overall, this study reveals that the new mechanism of FH regulating gene tranion, and illustrate clearly how tumor cells sustain tumor growth by OGT glycosylated FH under glucose deficiency.

Dr. Wang ting and Dr. Yu qiujing are the first authors of the paper, while Researcher Jiang Yuhui and Dr. Wang Ting are the co-authors. Many professers are involved in this study including Liao Lujian of East China Normal University,Qin Yue of Shanghai Academy of Life Sciences, and Academician Liu Xinyuan. The research has been financedby the Department of Organization of CPC, National Natural Science Foundation and Shanghai Science and Technology Commission.