METTL3 facilitates immunosurveillance by inhibiting YTHDF2-mediated NLRC5 mRNA degradation in endometrial cancer

被引:18
|
作者
Zhan, Lei [1 ,2 ,3 ,4 ,5 ,6 ,7 ]
Zhang, Jing [2 ]
Zhang, Jun-Hui [1 ,3 ,4 ,5 ,6 ,7 ]
Liu, Xiao-Jing [2 ]
Guo, Bao [2 ]
Chen, Jia-Hua [2 ]
Tang, Zhen-Hai [8 ]
Wang, Wen-Yan [2 ]
Wang, Qing-Yuan [2 ]
Wei, Bing [2 ]
Cao, Yun-Xia [1 ,3 ,4 ,5 ,6 ,7 ]
机构
[1] Anhui Med Univ, Affiliated Hosp 1, Dept Obstet & Gynecol, 218 Jixi Rd, Hefei 230022, Anhui, Peoples R China
[2] Anhui Med Univ, Affiliated Hosp 2, Dept Obstet & Gynecol, 678 Furong Rd, Hefei 230601, Anhui, Peoples R China
[3] Anhui Med Univ, NHC Key Lab Study Abnormal Gametes & Reprod Tract, 81 Meishan Rd, Hefei 230032, Anhui, Peoples R China
[4] Anhui Med Univ, Key Lab Populat Hlth Life Cycle, Minist Educ Peoples Republ China, 81 Meishan Rd, Hefei 230032, Anhui, Peoples R China
[5] Anhui Prov Key Lab Reprod Hlth & Genet, 81 Meishan Rd, Hefei 230032, Anhui, Peoples R China
[6] Anhui Prov Engn Res Ctr Biopreservat & Artificial, 81 Meishan Rd, Hefei 230032, Anhui, Peoples R China
[7] Anhui Prov Inst Translat Med, 81 Meishan Rd, Hefei 230032, Anhui, Peoples R China
[8] Ctr Sci Res Anhui Med Univ, 218 Jixi Rd, Hefei 230022, Anhui, Peoples R China
关键词
Endometrial cancer; N6-methyladenosine; N6-adenosine-methyltransferase-like; 3; YTH domain-containing family 2; NLR family CARD domain-containing 5; Immunosurveillance; Biomarker; Immunotherapy;
D O I
10.1186/s40364-023-00479-4
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background N6-methyladenosine (m6A) methylation is the most abundant chemical posttranscriptional modification of mRNA, and it is associated with the regulation of the immune response to tumors. However, the function of m6A modification in the immune response to endometrial cancer (EC) remains unknown. Our study investigated the immunological role of methyltransferase-like 3 (METTL3) in EC and the underlying molecular mechanism. Methods We investigated the correlation between the expression of METTL3 and CD8 by using an endometrial tissue microarray cohort. Next, we investigated the role and mechanism of METTL3 in the immune response to EC using a mouse tumor model and a CD8(+) T cell-EC cell coculture system after METTL3 overexpression or depletion. Additionally, RNA immunoprecipitation (RIP), methylated RIP, and RNA stability experiments were used to investigate the mechanism underlying the function of METTL3 in immunosurveillance of EC. Results METTL3 levels were downregulated in EC patients, low levels of METTL3 were correlated with poor prognosis in EC patients. There was a positive correlation between METTL3 expression and CD8 expression. Overexpression of METTL3 in the EC cell and CD8(+) T cell coculture system inhibited EC cell proliferation, migration, and promoted CD8(+) T-cell proliferation, and in vivo, METTL3 overexpression increased CD8(+) T cell proportions and inhibited EC progression; however, genetic depletion of METTL3 exerted the opposite effects. NLR family CARD domain-containing 5 (NLRC5) was identified as a target of METTL3-mediated m6A modification. The degradation of NLRC5 was increased by YTH domain-containing family 2 (YTHDF2). Conclusions Overall, METTL3, YTHDF2, and NLRC5 have potential to be the diagnostic and prognostic biomarkers for EC. METTL3 facilitated the m6A modifications of NLRC5 and inhibited its degradation through a YTHDF2-dependent mechanism in EC. Genetic overexpression of METTL3 attenuated the immune evasion of EC by promoting NLRC5-mediated immunosurveillance, suggesting that the METTL3/YTHDF2/NLRC5 axis is a promising target of immunotherapy in EC.
引用
收藏
页数:5
相关论文
共 20 条
  • [11] METTL3/YTHDF2 m6A axis promotes the malignant progression of bladder cancer by epigenetically suppressing RRAS
    Chen, Jie-Xun
    Chen, Dong-Ming
    Wang, Dong
    Xiao, Yi
    Zhu, Shuai
    Xu, Xian-Lin
    ONCOLOGY REPORTS, 2023, 49 (05)
  • [12] METTL3/YTHDF2 m6A axis accelerates colorectal carcinogenesis through epigenetically suppressing YPEL5
    Zhou, Dan
    Tang, Weiwei
    Xu, Yidan
    Xu, Yajie
    Xu, Binbin
    Fu, Shanshan
    Wang, Yanting
    Chen, Fangfang
    Chen, Yongxiong
    Han, Yinshu
    Wang, Gueyhorng
    MOLECULAR ONCOLOGY, 2021, 15 (08) : 2172 - 2184
  • [13] The N6-methyladenosine writer METTL3 promotes breast cancer progression through YTHDF2-dependent posttranscriptional silencing of GSDMD
    Shuai, You
    Ma, Zhonghua
    Ju, Jie
    Li, Chunxiao
    Bai, Xiaorong
    Yue, Jian
    Wang, Xue
    Yuan, Peng
    Qian, Haili
    APOPTOSIS, 2025, 30 (1-2) : 226 - 238
  • [14] Mettl3 inhibits the apoptosis and autophagy of chondrocytes in inflammation through mediating Bcl2 stability via Ythdf1-mediated m6A modification
    He, Ying
    Wang, Wei
    Xu, Xiaoxiao
    Yang, Beining
    Yu, Xijie
    Wu, Yanru
    Wang, Jiawei
    BONE, 2022, 154
  • [15] METTL3 and METTL14-mediated N6-methyladenosine modification of SREBF2-AS1 facilitates hepatocellular carcinoma progression and sorafenib resistance through DNA demethylation of SREBF2
    Wu, Xianjian
    Zeng, Min
    Wei, Yunyu
    Lu, Rongzhou
    Huang, Zheng
    Huang, Lizheng
    Huang, Yanyan
    Lu, Yuan
    Li, Wenchuan
    Wei, Huamei
    Pu, Jian
    SCIENTIFIC REPORTS, 2024, 14 (01)
  • [16] METTL3 promotes the growth and metastasis of pancreatic cancer by regulating the m6A modification and stability of E2F5
    Tang, Yan
    Gao, Guo
    Xia, Wen-Wen
    Wang, Jing-Bo
    CELLULAR SIGNALLING, 2022, 99
  • [17] m6A methyltransferase METTL3 promotes oral squamous cell carcinoma progression through enhancement of IGF2BP2-mediated SLC7A11 mRNA stability
    Xu, Le
    Li, Qingdang
    Wang, Yifei
    Wang, Lin
    Guo, Yuxing
    Yang, Rong
    Zhao, Na
    Ge, Na
    Wang, Yixiang
    Guo, Chuanbin
    AMERICAN JOURNAL OF CANCER RESEARCH, 2021, 11 (11): : 5282 - +
  • [18] Longnon-coding RNA BLACAT2 promotes gastric cancer progression via the miR-193b-5p/METTL3 pathway
    Hu, Hao
    Kong, Qi
    Huang, Xiao-xu
    Zhang, Hao-ran
    Hu, Kai-feng
    Jing, Yan
    Jiang, Yang-fan
    Peng, Yue
    Wu, Long-chao
    Fu, Qi-sheng
    Xu, Li
    Xia, Ya-bin
    JOURNAL OF CANCER, 2021, 12 (11): : 3209 - 3221
  • [19] METTL3-mediated m6A modification of Bcl-2 mRNA promotes non-small cell lung cancer progression
    Zhang, Yongxi
    Liu, Shuyuan
    Zhao, Tiesuo
    Dang, Chengxue
    ONCOLOGY REPORTS, 2021, 46 (02)
  • [20] FBW7/GSK3β mediated degradation of IGF2BP2 inhibits IGF2BP2-SLC7A5 positive feedback loop and radioresistance in lung cancer
    Zhou, Zhiyuan
    Zhang, Bin
    Deng, Yue
    Deng, Suke
    Li, Jie
    Wei, Wenwen
    Wang, Yijun
    Wang, Jiacheng
    Feng, Zishan
    Che, Mengjie
    Yang, Xiao
    Meng, Jingshu
    Li, Yan
    Hu, Yan
    Sun, Yajie
    Wen, Lu
    Huang, Fang
    Sheng, Yuhan
    Wan, Chao
    Yang, Kunyu
    JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 2024, 43 (01)