Bacteria pathogens drive host colonic epithelial cell promoter hypermethylation of tumor suppressor genes in colorectal cancer
Xiaoxuan Xia,
William Ka Kei Wu,
Sunny Hei Wong,
Dabin Liu,
Thomas Ngai Yeung Kwong,
Geicho Nakatsu,
Pearlly S. Yan,
Yu-Ming Chuang,
Michael Wing-Yan Chan,
Olabisi Oluwabukola Coker,
Zigui Chen,
Yun Kit Yeoh,
Liuyang Zhao,
Xiansong Wang,
Wing Yin Cheng,
Matthew Tak Vai Chan,
Paul Kay Sheung Chan,
Joseph Jao Yiu Sung,
Maggie Haitian Wang,
Jun Yu
Affiliations
Xiaoxuan Xia
Division of Biostatistics, Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, The Chinese University of Hong Kong
William Ka Kei Wu
Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong
Sunny Hei Wong
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong
Dabin Liu
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong
Thomas Ngai Yeung Kwong
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong
Geicho Nakatsu
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong
Pearlly S. Yan
Division of Hematology, Department of Internal Medicine, The Ohio State University
Yu-Ming Chuang
Department of Biomedical Sciences, National Chung Cheng University
Michael Wing-Yan Chan
Department of Biomedical Sciences, National Chung Cheng University
Olabisi Oluwabukola Coker
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong
Zigui Chen
Department of Microbiology, The Chinese University of Hong Kong
Yun Kit Yeoh
Department of Microbiology, The Chinese University of Hong Kong
Liuyang Zhao
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong
Xiansong Wang
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong
Wing Yin Cheng
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong
Matthew Tak Vai Chan
Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong
Paul Kay Sheung Chan
Department of Microbiology, The Chinese University of Hong Kong
Joseph Jao Yiu Sung
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong
Maggie Haitian Wang
Division of Biostatistics, Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, The Chinese University of Hong Kong
Jun Yu
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong
Abstract Background Altered microbiome composition and aberrant promoter hypermethylation of tumor suppressor genes (TSGs) are two important hallmarks of colorectal cancer (CRC). Here we performed concurrent 16S rRNA gene sequencing and methyl-CpG binding domain-based capture sequencing in 33 tissue biopsies (5 normal colonic mucosa tissues, 4 pairs of adenoma and adenoma-adjacent tissues, and 10 pairs of CRC and CRC-adjacent tissues) to identify significant associations between TSG promoter hypermethylation and CRC-associated bacteria, followed by functional validation of the methylation-associated bacteria. Results Fusobacterium nucleatum and Hungatella hathewayi were identified as the top two methylation-regulating bacteria. Targeted analysis on bona fide TSGs revealed that H. hathewayi and Streptococcus spp. significantly correlated with CDX2 and MLH1 promoter hypermethylation, respectively. Mechanistic validation with cell-line and animal models revealed that F. nucleatum and H. hathewayi upregulated DNA methyltransferase. H. hathewayi inoculation also promoted colonic epithelial cell proliferation in germ-free and conventional mice. Conclusion Our integrative analysis revealed previously unknown epigenetic regulation of TSGs in host cells through inducing DNA methyltransferase by F. nucleatum and H. hathewayi, and established the latter as CRC-promoting bacteria. Video abstract.
