ANKLE1 N6 -Methyladenosine-related variant is associated with colorectal cancer risk by maintaining the genomic stability.
The N6 -Methyladenosine (m6 A) modification plays an important role in many biological processes, especially tumor development. However, little is still known about how it affects colorectal cancer (CRC) carcinogenesis. Here, we first systematically investigate the association of variants related to m6 A modification with the CRC risk in 1,062 CRC cases and 2,184 controls by using our exome-wide association data and followed by two replication sets including 7,341 CRC cases and 7,902 controls. The variant rs8100241 located in ANKLE1 was significantly associated with CRC risk (odds ratio = 0.88, 95% confidence interval = 0.84-0.92, p = 4.85 × 10-8 ) in 8,403 cases and 10,086 controls. This variant was previously identified to be associated with the susceptibility of breast cancer with BRCA1 mutation triple negative breast cancer. Further functional analysis indicated that overexpression of the rs8100241[A] allele significantly increased the ANKLE1 m6 A level and facilitated the ANKLE1 protein expression compared to that of rs8100241[G] allele. We further found the ANKLE1 m6 A modification was catalyzed by the "writer" complex (METTL3, METTL14, or WTAP) and recognized by the "reader" YTHDF1. Mechanistically, we found that the ANKLE1 functions as a potential tumor suppressor that inhibits cell proliferation and facilitates the genomic stability. An elevated frequency of micronucleated cells, increased cell proliferation, and colony formation ability were observed when ANKLE1 knockdown. Our study illustrated that the germline missense variant can increase CRC risk by influencing ANKLE1 m6 A level, highlighting a clinical potential of variants-associated m6 A modification as a risk marker for CRC prevention.
['Tian|Jianbo|J|', 'Ying|Pingting|P|', 'Ke|Juntao|J|', 'Zhu|Ying|Y|', 'Yang|Yang|Y|', 'Gong|Yajie|Y|', 'Zou|Danyi|D|', 'Peng|Xiating|X|', 'Yang|Nan|N|', 'Wang|Xiaoyang|X|', 'Mei|Shufang|S|', 'Zhang|Yuxing|Y|', 'Wang|Changyi|C|', 'Zhong|Rong|R|', 'Chang|Jiang|J|0000-0001-8551-9458', 'Miao|Xiaoping|X|0000-0002-6818-9722']
D000241:Adenosine D000368:Aged D063646:Carcinogenesis D016022:Case-Control Studies D049109:Cell Proliferation D015179:Colorectal Neoplasms D019175:DNA Methylation D004720:Endonucleases D044127:Epigenesis, Genetic D005260:Female D015972:Gene Expression Regulation, Neoplastic D055785:Gene Knockdown Techniques D020022:Genetic Predisposition to Disease D042822:Genomic Instability D045325:HCT116 Cells D006801:Humans D008297:Male D008875:Middle Aged D020641:Polymorphism, Single Nucleotide
ANKLE1 colorectal cancer genomic stability N6-Methyladenosine