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.

中文翻译：

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Setd2的缺失促进了胰腺癌发生过程中Kras诱导的腺泡-导管化生和上皮-间质转化

目的 SETD2 是唯一的组蛋白 H3K36 三甲基转移酶，在人类癌症中经常发生突变或缺失，包括胰腺导管腺癌 (PDAC)。然而，SETD2/H3K36me3 改变是否导致 PDAC 仍然很大程度上未知。设计 TCGA(PAAD) 公共数据库和具有 SETD2/H3K36me3 染色的 PDAC 组织阵列用于研究 SETD2 在 PDAC 中的临床相关性。此外，为了确定 SETD2 在 PDAC 致癌作用中的作用，我们将条件性 Setd2 基因敲除小鼠（Pdx cre Setd2 flox/flox）与 Kras G12D 小鼠进行了交叉试验。此外，为了检查 SETD2 在导管化生后的作用，使用 Crisp/cas9 来消耗 PDAC 细胞中的 Setd2。进行了 RNA-seq 和 H3K36me3 ChIP-seq 以揭示该机制。结果 SETD2 突变/低表达与 PDAC 患者的不良预后相关。下一个，我们发现 Setd2 在 Kras 驱动的胰腺癌发生中充当推定的肿瘤抑制因子。从机制上讲，腺泡细胞中的 Setd2 缺失促进了 Kras 诱导的腺泡到导管的重编程，主要是通过 Fbxw7 的表观遗传失调。此外，胰腺癌细胞中的 Setd2 消融通过 Ctnna1 的表观遗传调控受损增强了上皮 - 间充质转化（EMT）。此外，Setd2 缺陷通过固有的细胞外基质 (ECM) 产生导致持续的 Akt 激活，这将有利于它们的转移。结论 总之，我们的研究结果突出了 SETD2 在胰腺癌发生过程中的功能，这将促进我们对 PDAC 表观遗传失调的理解。此外，它还可能为针对患有 SETD2 缺陷的 PDAC 患者开发有针对性的、患者定制的疗法铺平道路。