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 (Pdx cre Setd2 flox/flox) together with Kras G12D 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/low expression 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.
- pancreatic cancer
- cancer genetics
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NN and PL contributed equally.
Contributors JX, NN and PL designed experiment and interpreted data; NN and PL performed most of the experiments; YY, RH, JS, JW, MY and LZ assisted in some experiments; L-WW, W-QG and ZZ provided the key materials; ZZ, GGX and AH assisted in some discussion; JX and NN wrote the manuscript; JX, LL and YS provided the overall guidance.
Funding This work was supported by Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning No TP2015007 (JX); Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support No 20161312 (JX); The Shanghai Youth Talent Support Program (JX); Shanghai Rising-Star Program No 19QA1408300 (NN); The Science and Technology Commission of Shanghai Municipality No 18140902700 and No 19140905500 (LL); State Key Laboratory of Oncogenes and Related Genes No KF01801 (LL); Innovation Research Plan supported by Shanghai Municipal Education Commission No ZXGF082101 (LL); National Natural Science Foundation of China No 81702938 and No 81770628 (JX), No 81772938 (LL), No 81802307 (PL), No 81874175 (YS) and No 81802317 (MY).
Competing interests None declared.
Ethics approval All protocols for animal use and euthanasia were reviewed and approved by RenJi Hospital Institutional Animal Care and Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This article has been corrected since it published Online First. The author name Li-Wei Wang has been corrected.
Patient consent for publication Not required.
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