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Brg1 controls stemness and metastasis of pancreatic cancer through regulating hypoxia pathway

Oncogene volume 42, pages 2139–2152 (2023)Cite this article

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. We previously reported that chromatin remodeler Brg1 is essential for acinar cell-derived PDAC formation in mice. However, the functional role of Brg1 in established PDAC and its metastasis remains unknown. Here, we investigated the importance of Brg1 for established PDAC by using a mouse model with a dual recombinase system. We discovered that Brg1 was a critical player for the cell survival and growth of spontaneously developed PDAC in mice. In addition, Brg1 was essential for metastasis of PDAC cells by inhibiting apoptosis in splenic injection and peritoneal dissemination models. Moreover, cancer stem-like property was compromised in PDAC cells by Brg1 ablation. Mechanistically, the hypoxia pathway was downregulated in Brg1-deleted mouse PDAC and BRG1-low human PDAC. Brg1 was essential for HIF-1α to bind to its target genes to augment the hypoxia pathway, which was important for PDAC cells to maintain their stem-like properties and to metastasize to the liver. Human PDAC cells with high BRG1 expression were more susceptible to BRG1 suppression. In conclusion, Brg1 plays a critical role for cell survival, stem-like property and metastasis of PDAC through the regulation of hypoxia pathway, and thus could be a novel therapeutic target for PDAC.

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Fig. 1: Brg1 plays an important role in the growth of spontaneously developed invasive PDAC in mice.
Fig. 2: Brg1 is critical for cell proliferation and survival of PDAC cells in vitro.
Fig. 3: Brg1 plays an essential role for liver metastasis of mouse PDAC cells by inhibiting apoptosis in vivo.
Fig. 4: Brg1 is critically important for cancer stem-like property of PDAC cells.
Fig. 5: Brg1 plays a critical role for metastasis and cancer stem-like property of PDAC cells through directly regulating the expression of HIF target genes.
Fig. 6: Brg1 directly regulates the expression of HIF target genes in PDAC cells.
Fig. 7: Brg1 expression is a predictive determinant of BRG1 knockdown efficacy of suppression of human PDAC cell proliferation and stem-like property.

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Data availability

All original microarray data were deposited in the Gene Expression Omnibus (GEO) at National Center for Biotechnology Information (NCBI) with series accession no. GSE199442. The complete ChIP-Seq data were deposited in the GEO at NCBI with series accession no. GSE199610.

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Acknowledgements

The authors thank all members of the Fukuda laboratory for technical assistance and helpful discussions. This work was supported in part by Grants-in-Aid KAKENHI (19H03639, 19K16712, 19K22619, 20H03659). It was also supported by Japan Agency for Medical Research and Development, the Project for Cancer Research and Therapeutic Evolution (18cm0106142h0001, 20cm0106177h0001, 20cm0106375h0001) and AMED-PRIME (20gm6010022h0003), Moonshot Research and Development Program (JPMJMS2022-1), and COI-NEXT (JPMJPF2018). It was also supported by Princess Takamatsu Cancer Research Fund (17-24924), the Mochida Foundation (2017bvAg), the Mitsubishi Foundation (201910037), the Uehara Foundation (201720143), the Naito Foundation (22205-1), the Kobayashi Foundation (203200700019), the Simizu Foundation (203180700103), the Japan Foundation for Applied Enzymology (203190700054), the SGH Foundation (203200700056), the Kanae Foundation (203190700083), the Bristol Myers Squibb (200190700011), the Ichiro Kanehara Foundation (20KI037), and the Takeda Foundation (201749741, 203200700045). A part of this study was conducted through the CORE Program of the Radiation Biology Center, Kyoto University.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Osamu Araki, Motoyuki Tsuda, Mayuki Omatsu, Mio Namikawa, Makoto Sono, Yuichi Fukunaga, Tomonori Masuda, Takaaki Yoshikawa, Munemasa Nagao, Satoshi Ogawa, Kenji Masuo, Norihiro Goto, Yu Muta, Yukiko Hiramatsu, Takahisa Maruno, Yuki Nakanishi, Akihisa Fukuda & Hiroshi Seno

  2. Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Yuichi Fukunaga

  3. Departments of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Sho Koyasu

  4. Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Toshihiko Masui & Etsuro Hatano

  5. Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany

    Dieter Saur

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Contributions

OA, MT, and AF conceived and designed the study. OA, MT, TY, MN, SO, YH, and TM performed the experiments and analyzed the data. MN, MS, YF, TM, MO, KM, YM, NG, and SK contributed reagents, materials, and analysis tools. TM and EH contributed surgical specimens. DS generated Pdx1-Flp, KrasFSF-G12D, Trp53frt, and Rosa26FSF-CreERT2 mice. OA wrote the paper and YN, AF, and HS revised it. AF organized the study.

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Correspondence to Akihisa Fukuda.

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This author discloses the following: YF is employed by Sumitomo Dainippon Pharma. The remaining authors disclose no competing interests.

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Araki, O., Tsuda, M., Omatsu, M. et al. Brg1 controls stemness and metastasis of pancreatic cancer through regulating hypoxia pathway. Oncogene 42, 2139–2152 (2023). https://doi.org/10.1038/s41388-023-02716-4

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