Kawai Munenori, Fukuda Akihisa, Ikeda Munehiro, Iimori Kei, Mizukoshi Kenta, Iwane Kosuke, Yamakawa Go, Omatsu Mayuki, Namikawa Mio, Sono Makoto, Masuda Tomonori, Fukunaga Yuichi, Nagao Munemasa, Araki Osamu, Yoshikawa Takaaki, Ogawa Satoshi, Hiramatsu Yukiko, Tsuda Motoyuki, Maruno Takahisa, Nakanishi Yuki, Saur Dieter, Tsuruyama Tatsuaki, Masui Toshihiko, Hatano Etsuro, Seno Hiroshi
Department of Gastroenterology and Hepatology and.
Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
J Clin Invest. 2025 Jun 2;135(11). doi: 10.1172/JCI177533.
Mutations in Polybromo 1 (PBRM1), a subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, are frequently observed in several cancers, including pancreatic ductal adenocarcinoma (PDAC). In this study, we demonstrated that pancreas-specific loss of Pbrm1 in mice harboring Kras mutations and Trp53 deletions accelerated the development of poorly differentiated PDAC, epithelial-mesenchymal transition (EMT), and metastasis, resulting in worsened prognosis. Pbrm1 loss in preexisting PDAC shifted the tumor grade from a well- to a poorly differentiated state and elevated vimentin expression. Pbrm1-null PDAC exhibited downregulation of apical junction genes and upregulation of EMT pathway genes, including the vimentin and squamous molecular subtype signature genes. Mechanistically, PBRM1 bound to the vimentin gene promoter and directly downregulated its expression. Furthermore, suppression of vimentin in Pbrm1-null PDAC cells reversed the dedifferentiation phenotype and reduced EMT and metastasis. Consistently, reduced PBRM1 expression correlated with high vimentin expression, poorly differentiated histology, a high recurrence rate, and reduced overall survival in human PDACs. Additionally, PDAC with PBRM1 deletion was associated with the aggressive squamous molecular subtype. Our data established PBRM1 as a tumor suppressor that controls tumor grade and metastasis of PDAC by regulating vimentin expression.
多溴1（PBRM1）是开关/蔗糖非发酵（SWI/SNF）染色质重塑复合物的一个亚基，其突变在包括胰腺导管腺癌（PDAC）在内的多种癌症中经常被观察到。在本研究中，我们证明，在携带Kras突变和Trp53缺失的小鼠中，胰腺特异性缺失Pbrm1会加速低分化PDAC的发展、上皮-间质转化（EMT）和转移，导致预后恶化。在已有的PDAC中缺失Pbrm1会使肿瘤分级从高分化转变为低分化状态，并提高波形蛋白的表达。Pbrm1基因缺失的PDAC表现出顶端连接基因的下调和EMT途径基因的上调，包括波形蛋白和鳞状分子亚型特征基因。从机制上讲，PBRM1与波形蛋白基因启动子结合并直接下调其表达。此外，在Pbrm1基因缺失的PDAC细胞中抑制波形蛋白可逆转去分化表型，并减少EMT和转移。一致地，在人类PDAC中，PBRM1表达降低与波形蛋白高表达、低分化组织学、高复发率和总生存期缩短相关。此外，PBRM1缺失的PDAC与侵袭性鳞状分子亚型相关。我们的数据确立了PBRM1作为一种肿瘤抑制因子，通过调节波形蛋白表达来控制PDAC的肿瘤分级和转移。
