Polybromo 1/vimentin axis dictates tumor grade, epithelial-mesenchymal transition, and metastasis in pancreatic cancer
Munenori Kawai, … , Etsuro Hatano, Hiroshi Seno
Munenori Kawai, … , Etsuro Hatano, Hiroshi Seno
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e177533. https://doi.org/10.1172/JCI177533.
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Research Article Gastroenterology Oncology

Polybromo 1/vimentin axis dictates tumor grade, epithelial-mesenchymal transition, and metastasis in pancreatic cancer

Abstract

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.

Authors

Munenori Kawai, Akihisa Fukuda, Munehiro Ikeda, Kei Iimori, Kenta Mizukoshi, Kosuke Iwane, Go Yamakawa, Mayuki Omatsu, Mio Namikawa, Makoto Sono, Tomonori Masuda, Yuichi Fukunaga, Munemasa Nagao, Osamu Araki, Takaaki Yoshikawa, Satoshi Ogawa, Yukiko Hiramatsu, Motoyuki Tsuda, Takahisa Maruno, Yuki Nakanishi, Dieter Saur, Tatsuaki Tsuruyama, Toshihiko Masui, Etsuro Hatano, Hiroshi Seno

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Figure 6

PBRM1 binds to the vimentin gene promoter to directly regulate its expression.

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PBRM1 binds to the vimentin gene promoter to directly regulate its expre...
(A) GSEA of PDAC cells from KPC and KPCPb–/– mice using “Hallmark gene sets.” NES, normalized enrichment score. *P < 0.05. (B) GSEA enrichment plots of the HALLMARK apical junction. FDR, false discovery rate. (C) GSEA of PDAC cells from KPC and KPCPb–/– mice using the vimentin gene set. (D) Quantitative real-time PCR analysis of the relative mRNA expression of Cdh1, Cdh2, Cldn4, Cldn7, Dsc2, and Dsg2 in KPCPb–/– (n = 3) PDAC cells compared with KPC (n = 3) PDAC cells. *P < 0.05, Student t test. Data shown as mean ± SE. (E) Quantitative real-time PCR analysis of the relative mRNA expression of Vim, Snai1, Snai2, and Twist1 in KPCPb–/– (n = 3) PDAC cells compared with KPC (n = 3) PDAC cells. *P < 0.05, Student t test. Data shown as mean ± SE. (F) Venn diagram of the analysis of genes bound by PBRM1 and differentially expressed genes identified by RNA-seq. Sixty-eight genes are bound by H3K27Ac out of the 164 genes that are bound by PBRM1 and upregulated in KPC PDAC cells and 25 genes are bound by H3K27ac out of 60 genes that are bound by PBRM1 and upregulated in KPCPb–/– PDAC cells. (G) ChIP data of the PBRM1 and H3K27ac binding region in the vimentin gene promoter and coding regions. TSS, transcription start site. (H) Representative vimentin staining in PDAC of KPC and KPCPb–/– mice. Scale bar: 50 μm. Data are representative of 3 independent experiments.