PDF(Pubmed)
Abstract：
Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis due to therapeutic resistance. We show that PDAC cells undergo global epigenetic reprogramming to acquire chemoresistance, a process that is driven at least in part by protein arginine methyltransferase 1 (PRMT1). Genetic or pharmacological PRMT1 inhibition impairs adaptive epigenetic reprogramming and delays acquired resistance to gemcitabine and other common chemo drugs. Mechanistically, gemcitabine treatment induces translocation of PRMT1 into the nucleus, where its enzymatic activity limits the assembly of chromatin-bound MAFF/BACH1 transcriptional complexes. Cut&Tag chromatin profiling of H3K27Ac, MAFF, and BACH1 suggests a pivotal role for MAFF/BACH1 in global epigenetic response to gemcitabine, which is confirmed by genetically silencing MAFF. PRMT1 and MAFF/BACH1 signature genes identified by Cut&Tag analysis distinguish gemcitabine-resistant from gemcitabine-sensitive patient-derived xenografts of PDAC, supporting the PRMT1-MAFF/BACH1 epigenetic regulatory axis as a potential therapeutic avenue for improving the efficacy and durability of chemotherapies in patients of PDAC.
摘要：
胰腺导管腺癌（PDAC）由于治疗耐药性而预后不佳。我们表明PDAC细胞经历全局表观遗传重编程以获得化学抗性，至少部分由蛋白质精氨酸甲基转移酶1(PRMT1)驱动的过程。遗传或药理学PRMT1抑制损害适应性表观遗传重编程并延迟对吉西他滨和其他常见化疗药物的获得性抗性。机械上,吉西他滨治疗诱导PRMT1易位进入细胞核，其中其酶活性限制了染色质结合的MAFF/BACH1转录复合物的组装。H3K27Ac的剪切和标记染色质分析，MAFF,和BACH1表明MAFF/BACH1在吉西他滨的全球表观遗传反应中的关键作用，这通过基因沉默MAFF得到证实。通过Cut&Tag分析鉴定的PRMT1和MAFF/BACH1特征基因区分吉西他滨耐药与吉西他滨敏感的患者来源的PDAC异种移植物，支持PRMT1-MAFF/BACH1表观遗传调节轴作为改善PDAC患者化疗疗效和持久性的潜在治疗途径.
