Loss of Setd2 promotes Kras-induced acinar-to-ductal metaplasia and epithelia–mesenchymal transition during pancreatic carcinogenesis

Abstract

ObjectiveSETD2, 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.DesignTCGA(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.ResultsSETD2 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.ConclusionTogether, 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.

Histone methyltransferase and drug resistance in cancers

“…The low expression of SETD2 leads to proliferative advantage, increased colony formation and accelerated leukemia development of fusion-protein expressing cancer cells in MLL [38]. Similar reports are common in cancers such as renal cell carcinoma and pancreatic cancer [39,40]. In addition to EZH2 and SETD2, KMTs such as G9a [41,42], MLL [43], DOT1L [44] and NSD1 [45] are associated with tumor development and progression.…”

Gene modules and non-coding RNAs involved in pancreatic tumorigenesis through acinar ductal metaplasia

“…Hdac11 has been shown as a novel target in antitumor therapy [39]. Loss of histone trimethyl transferase, H3K36, facilitated ADM formation through epigenetic dysregulation and led to extracellular matrix (ECM) production in PDAC [40].…”

SETD2 deficiency impairs β-catenin destruction complex to facilitate renal cell carcinoma formation

“…SETD2 fl/fl mice were generated by Shanghai Biomodel Organism Co. using conventional homologous recombination in ES cells as previously reported (Niu et al, 2019…”

“…Our previous studies have also reported that SETD2 is pivotal for bone marrow mesenchymal stem cells differentiation (Wang et al, 2018), maternal epigenome, genomic imprinting and embryonic development (Xu et al, 2019), sperm development (Zuo et al, 2018), and V(D)J recombination in normal lymphocyte development (Ji et al, 2019). SETD2 loss leads to pancreatic carcinogenesis (Niu et al, 2019). Mutations or functional loss of SETD2 produces dysfunctional tumor tissue proteins, causing tumorigenesis, progression, chemotherapy resistance and unfavorable prognosis (Chen et al, 2020).…”