TY - JOUR
T1 - The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma
AU - Wang, Shiyan
AU - Zeng, Yong
AU - Zhu, Lin
AU - Zhang, Min
AU - Zhou, Lei
AU - Yang, Weixiong
AU - Luo, Weishan
AU - Wang, Lina
AU - Liu, Yanming
AU - Zhu, Helen
AU - Xu, Xin
AU - Su, Peiran
AU - Zhang, Xinyue
AU - Ahmed, Musaddeque
AU - Chen, Wei
AU - Chen, Moliang
AU - Chen, Sujun
AU - Slobodyanyuk, Mykhaylo
AU - Xie, Zhongpeng
AU - Guan, Jiansheng
AU - Zhang, Wen
AU - Khan, Aafaque Ahmad
AU - Sakashita, Shingo
AU - Liu, Ni
AU - Pham, Nhu-An
AU - Boutros, Paul C.
AU - Ke, Zunfu
AU - Moran, Michael F.
AU - Cai, Zongwei
AU - Cheng, Chao
AU - Yu, Jun
AU - Tsao, Ming S.
AU - He, Housheng H.
N1 - This work was supported by the Princess Margaret Cancer Foundation (886012001223 to H.H. He), Canada Foundation for Innovation and Ontario Research Fund (CFI32372 to H.H. He), NSERC discovery grants (498706 to H.H. He; 06305 to M.F. Moran), Canadian Cancer Society innovation grants (703800 to H.H. He), IMPACT grant (701595 to M.S. Tsao), CIHR operating grants (142246, 152863, 152864, and 159567 to H.H. He; 364778 to M.F. Moran), Foundation grant (FDN-148395 to M.S. Tsao), and Terry Fox New Frontiers Program Project Grant (1090 and 1124 to H.H. He). H.H. He was supported by TFRI New Investigator Awards and CIHR New Investigator Awards. H.H. He holds an OMIR Early Researcher Award. Y. Zeng was supported by a postdoctoral fellowship by Princess Margaret Cancer Foundation. We thank Jonathan R. Krieger (SPARC BioCentre, Hospital for Sick Children, Toronto Canada) for help with MS data analysis.
Publisher Copyright:
©2024 The Authors; Published by the American Association for Cancer Research
PY - 2024/11/1
Y1 - 2024/11/1
N2 - Comprehensive N6-methyladenosine (m6A) epitranscriptomic profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 nonneoplastic lung tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating the corresponding transcriptomic, proteomic, and extensive clinical annotations. We identified distinct clusters and genes that were exclusively linked to disease progression through m6A modifications. In comparison with nonneoplastic lung tissues, we identified 430 transcripts to be hypo-methylated and 222 to be hyper-methylated in tumors. Among these genes, EML4 emerged as a novel metastatic driver, displaying significant hypermethylation in tumors. m6A modification promoted the translation of EML4, leading to its widespread overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics by interacting with ARPC1A, enhancing lamellipodia formation, cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. METTL3 small-molecule inhibitor markedly diminished both EML4 m6A and protein abundance and efficiently suppressed lung metastases in vivo.Significance: Our study reveals a dynamic and functional epitranscriptomic landscape in LUAD, offering a valuable resource for further research in the field. We identified EML4 hypermethylation as a key driver of tumor metastasis, highlighting a novel therapeutic strategy of targeting EML4 to prevent LUAD metastasis.
AB - Comprehensive N6-methyladenosine (m6A) epitranscriptomic profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 nonneoplastic lung tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating the corresponding transcriptomic, proteomic, and extensive clinical annotations. We identified distinct clusters and genes that were exclusively linked to disease progression through m6A modifications. In comparison with nonneoplastic lung tissues, we identified 430 transcripts to be hypo-methylated and 222 to be hyper-methylated in tumors. Among these genes, EML4 emerged as a novel metastatic driver, displaying significant hypermethylation in tumors. m6A modification promoted the translation of EML4, leading to its widespread overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics by interacting with ARPC1A, enhancing lamellipodia formation, cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. METTL3 small-molecule inhibitor markedly diminished both EML4 m6A and protein abundance and efficiently suppressed lung metastases in vivo.Significance: Our study reveals a dynamic and functional epitranscriptomic landscape in LUAD, offering a valuable resource for further research in the field. We identified EML4 hypermethylation as a key driver of tumor metastasis, highlighting a novel therapeutic strategy of targeting EML4 to prevent LUAD metastasis.
UR - http://www.scopus.com/inward/record.url?scp=85208291284&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-23-1212
DO - 10.1158/2159-8290.CD-23-1212
M3 - Journal article
C2 - 38922581
SN - 2159-8274
VL - 14
SP - 2279
EP - 2299
JO - Cancer Discovery
JF - Cancer Discovery
IS - 11
ER -
