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Research Work on Pancreatic Cancer Produced by SJTU

August 14, 2019      Author: Li Li

On July 11, 2019, Li Li’s research team from the School of Biomedical Engineering, SJTU, and Xue Jing and Sun Yongwei’s research team from the Renji Hospital affiliated to the School of Medicine, SJTU published a paper on GUT titled “Loss of SETD2 promotes KRAS-induced acinar-to-ductal metaplasia and epithelia-mesenchymal transition during pancreatic carcinogenesis”. The paper indicates that the loss of SETD2 along with the KARS will promote the development of pancreatic cancer and that there are different functions and mechanisms of SETD2 in the beginning and transition of pancreatic cancer.

Associate Researcher Niu Ningning and Doctor Lu Ping are the co-authors of the paper; and Researcher Xue Jing, Associate Researcher Li Li and Director Sun Yongwei are the co-corresponding authors.



Objective SETD2, the sole histone H3K36 trimethyltransferase, is frequently mutated or deleted in human cancer, including pancreatic ductal adenocarcinoma (PDAC). However, whether SETD2/H3K36me3 alteration results in PDAC remains largely unknown.

Design TCGA(PAAD) public database and PDAC tissue array with SETD2/H3K36me3 staining were used to investigate the clinical relevance of SETD2 in PDAC. Furthermore, to define the role of SETD2 in the carcinogenesis of PDAC, we crossed conditional Setd2 knockout mice (PdxcreSetd2flox/flox) together with KrasG12D mice. Moreover, to examine the role of SETD2 after ductal metaplasia, Crisp/cas9 was used to deplete Setd2 in PDAC cells. RNA-seq and H3K36me3 ChIP-seq were performed to uncover the mechanism.

Results SETD2 mutant/lowexpression was correlated with poor prognosis in patients with PDAC. Next, we found that Setd2 acted as a putative tumour suppressor in Kras-driven pancreatic carcinogenesis. Mechanistically, Setd2 loss in acinar cells facilitated Kras-induced acinar-to-ductal reprogramming, mainly through epigenetic dysregulation of Fbxw7. Moreover, Setd2 ablation in pancreatic cancer cells enhanced epithelia–mesenchymal transition (EMT) through impaired epigenetic regulation of Ctnna1. In addition, Setd2 deficiency led to sustained Akt activation via inherent extracellular matrix (ECM) production, which would favour their metastasis.


Conclusion Together, our findings highlight the function of SETD2 during pancreatic carcinogenesis, which would advance our understanding of epigenetic dysregulation in PDAC. Moreover, it may also pave the way for development of targeted, patients-tailored therapies for PDAC patients with SETD2 deficiency.

Paper Link: http://dx.doi.org/10.1136/gutjnl-2019-318362



Translated by Zhu Fengyan  Reviewed by Wang Bingyu