Brg1 is required to maintain colorectal cancer stem cells

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

doi:10.1002/path.5759

Brg1 is required to maintain colorectal cancer stem cells

J Pathol. 2021 Nov;255(3):257-269. doi: 10.1002/path.5759. Epub 2021 Aug 20.

Authors

Takaaki Yoshikawa¹, Akihisa Fukuda¹, Mayuki Omatsu¹, Mio Namikawa¹, Makoto Sono¹, Yuichi Fukunaga^{1

2}, Tomonori Masuda¹, Osamu Araki¹, Munemasa Nagao¹, Satoshi Ogawa¹, Kenji Masuo^{1

3}, Norihiro Goto¹, Yukiko Hiramatsu¹, Yu Muta¹, Motoyuki Tsuda¹, Takahisa Maruno¹, Yuki Nakanishi¹, Kenji Kawada⁴, Shigeo Takaishi³, Hiroshi Seno¹

Affiliations

¹ Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
² Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
³ Laboratory for Malignancy Control Research (DSK Project), Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁴ Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

PMID: 34415580
DOI: 10.1002/path.5759

Abstract

Tumor cells capable of self-renewal and continuous production of progeny cells are called tumor stem cells (TSCs) and are considered to be potential therapeutic targets. However, the mechanisms underlying the survival and function of TSCs are not fully understood. We previously reported that chromatin remodeling regulator Brg1 is essential for intestinal stem cells in mice and Dclk1 is an intestinal TSC marker. In this study, we investigated the role of Brg1 in Dclk1⁺ intestinal tumor cells for the maintenance of intestinal tumors in mice. Specific ablation of Brg1 in Dclk1⁺ intestinal tumor cells reduced intestinal tumors in Apc^Min mice, and continuous ablation of Brg1 maintained the reduction of intestinal tumors. Lineage tracing in the context of Brg1 ablation in Dclk1⁺ intestinal tumor cells revealed that Brg1-null Dclk1⁺ intestinal tumor cells did not give rise to their descendent tumor cells, indicating that Brg1 is essential for the self-renewal of Dclk1⁺ intestinal tumor cells. Five days after Brg1 ablation, we observed increased apoptosis in Dclk1⁺ tumor cells. Furthermore, Brg1 was crucial for the stemness of intestinal tumor cells in a spheroid culture system. BRG1 knockdown also impaired cell proliferation and increased apoptosis in human colorectal cancer (CRC) cells. Microarray analysis revealed that apoptosis-related genes were upregulated and stem cell-related genes were downregulated in human CRC cells by BRG1 suppression. Consistently, high BRG1 expression correlated with poor disease-specific survival in human CRC patients. These data indicate that Brg1 plays a crucial role in intestinal TSCs in mice by inhibiting apoptosis and is critical for cell survival and stem cell features in human CRC cells. Thus, BRG1 represents a new therapeutic target for human CRC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: Brg1; chromatin remodeling regulator; colorectal cancer; tumor stem cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Colorectal Neoplasms / pathology*
DNA Helicases / metabolism*
Mice
Neoplastic Stem Cells / pathology*
Nuclear Proteins / metabolism*
Transcription Factors / metabolism*

Substances

Nuclear Proteins
Transcription Factors
SMARCA4 protein, human
Smarca4 protein, mouse
DNA Helicases