Bacteria pathogens drive host colonic epithelial cell promoter hypermethylation of tumor suppressor genes in colorectal cancer
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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.

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.

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.
Acceptance Date26/04/2020
All Author(s) ListXia XX, Wu WKK, Wong SH, Liu D, Kwong TNY, Nakatsu G, Yan PS, Chuang YM, Chan MWY, Coker O, Chen ZG, Yeoh YK, Zhao LY, Wang XS, Cheng WY, Chan MTV, Chan PKS, Sung JJY, Wang MHT, Yu J
Journal nameMicrobiome
Volume Number8
Article number108
LanguagesEnglish-United Kingdom
KeywordsColorectal cancer, Microbiota, DNA methylation, MBDCap-Seq, DNMT

Last updated on 2021-18-09 at 00:04