The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation

被引：598

作者：

Liu, Tao ^{[1
]}

Wei, Qinglv ^{[2
]}

Jin, Jing ^{[3
]}

Luo, Qingya ^{[1
]}

Liu, Yi ^{[1
,2
]}

Yang, Yu ^{[2
]}

Cheng, Chunming ^{[4
,5
]}

Li, Lanfang ^{[1
]}

Pi, Jingnan ^{[6
,7
]}

Si, Yanmin ^{[6
,7
]}

Xiao, Hualiang ^{[8
]}

Li, Li ^{[1
]}

Rao, Shuan ^{[9
]}

Wang, Fang ^{[6
,7
]}

Yu, Jianhua ^{[10
]}

Yu, Jia ^{[6
,7
]}

Zou, Dongling ^{[11
,12
,13
]}

Yi, Ping ^{[1
,2
]}

机构：

[1] Army Med Univ, Daping Hosp, Res Inst Surg, Dept Obstet & Gynecol, Chongqing 400042, Peoples R China

[2] Chongqing Med Univ, Dept Obstet & Gynecol, Affiliated Hosp 3, Chongqing 401120, Peoples R China

[3] Chinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China

[4] Ohio State Univ, Dept Radiat Oncol, James Comprehens Canc Ctr, Columbus, OH 43210 USA

[5] Ohio State Univ, Coll Med, James Comprehens Canc Ctr, Columbus, OH 43210 USA

[6] Chinese Acad Med Sci, Inst Basic Med Sci, Dept Biochem, Beijing 100005, Peoples R China

[7] Peking Union Med Coll, Beijing 100005, Peoples R China

[8] Army Med Univ, Daping Hosp, Res Inst Surg, Dept Pathol, Chongqing 400042, Peoples R China

[9] Southern Med Univ, Nanfang Hosp, Dept Thorac Surg, Guangzhou 510515, Guangdong, Peoples R China

[10] City Hope Natl Med Ctr, Dept Hematol & Hematopoiet Cell Transplantat, Duarte, CA 91010 USA

[11] Chongqing Univ, Dept Gynecol Oncol, Canc Hosp, Chongqing 400030, Peoples R China

[12] Chongqing Canc Inst, Chongqing 400030, Peoples R China

[13] Chongqing Canc Hosp, Chongqing 400030, Peoples R China

来源：

NUCLEIC ACIDS RESEARCH | 2020年 / 48卷 / 07期

基金：

国家重点研发计划;

关键词：

MESSENGER-RNA; NUCLEAR-RNA; METTL3; DIFFERENTIATION; DEMETHYLASE; TRANSITION; CARCINOMA; ALKBH5; TARGET; FATE;

D O I：

10.1093/nar/gkaa048

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

N-6-Methyladenosine (m(6)A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m(6)A in human tumorigenesis. However, whether m(6)A, especially its `reader' YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1. YTHDF1 augments the translation of EIF3C in an m(6)A-dependent manner by binding to m(6)A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. YTHDF1 is frequently amplified in ovarian cancer and up-regulation of YTHDF1 is associated with the adverse prognosis of ovarian cancer patients. Furthermore, the protein but not the RNA abundance of EIF3C is increased in ovarian cancer and positively correlates with the protein expres- sion of YTHDF1 in ovarian cancer patients, suggesting modification of EIF3C mRNA is more relevant to its role in cancer. Collectively, we identify the novel YTHDF1-EIF3C axis critical for ovarian cancer progression which can serve as a target to develop therapeutics for cancer treatment.

引用

页码：3816 / 3831

页数：16

共 54 条

[1] m6A RNA Modification Controls Cell Fate Transition in Mammalian Embryonic Stem Cells [J].

Batista, Pedro J. ;

Molinie, Benoit ;

Wang, Jinkai ;

Qu, Kun ;

Zhang, Jiajing ;

Li, Lingjie ;

Bouley, Donna M. ;

Lujan, Ernesto ;

Haddad, Bahareh ;

Daneshvar, Kaveh ;

Carter, Ava C. ;

Flynn, Ryan A. ;

Zhou, Chan ;

Lim, Kok-Seong ;

Dedon, Peter ;

Wernig, Marius ;

Mullen, Alan C. ;

Xing, Yi ;

Giallourakis, Cosmas C. ;

Chang, Howard Y. .

CELL STEM CELL, 2014, 15 (06) :707-719

[2] Ovarian Cancer Cell Line Panel (OCCP): Clinical Importance of In Vitro Morphological Subtypes [J].

Beaufort, Corine M. ;

Helmijr, Jean C. A. ;

Piskorz, Anna M. ;

Hoogstraat, Marlous ;

Ruigrok-Ritstier, Kirsten ;

Besselink, Nicolle ;

Murtaza, Muhammed ;

van IJcken, Wilfred F. J. ;

Heine, Anouk A. J. ;

Smid, Marcel ;

Koudijs, Marco J. ;

Brenton, James D. ;

Berns, Els M. J. J. ;

Helleman, Jozien .

PLOS ONE, 2014, 9 (09)

[3] Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[4] Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer [J].

Bowtell, David D. ;

Boehm, Steffen ;

Ahmed, Ahmed A. ;

Aspuria, Paul-Joseph ;

Bast, Robert C., Jr. ;

Beral, Valerie ;

Berek, Jonathan S. ;

Birrer, Michael J. ;

Blagden, Sarah ;

Bookman, Michael A. ;

Brenton, James D. ;

Chiappinelli, Katherine B. ;

Martins, Filipe Correia ;

Coukos, George ;

Drapkin, Ronny ;

Edmondson, Richard ;

Fotopoulou, Christina ;

Gabra, Hani ;

Galon, Jerome ;

Gourley, Charlie ;

Heong, Valerie ;

Huntsman, David G. ;

Iwanicki, Marcin ;

Karlan, Beth Y. ;

Kaye, Allyson ;

Lengyel, Ernst ;

Levine, Douglas A. ;

Lu, Karen H. ;

McNeish, Iain A. ;

Menon, Usha ;

Narod, Steven A. ;

Nelson, Brad H. ;

Nephew, Kenneth P. ;

Pharoah, Paul ;

Powell, Daniel J., Jr. ;

Ramos, Pilar ;

Romero, Iris L. ;

Scott, Clare L. ;

Sood, Anil K. ;

Stronach, Euan A. ;

Balkwill, Frances R. .

NATURE REVIEWS CANCER, 2015, 15 (11) :668-679

[5] The m6A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-κB/MYC signaling network [J].

Cheng, Maosheng ;

Sheng, Lu ;

Gao, Qian ;

Xiong, Qiuchan ;

Zhang, Haojie ;

Wu, Mingqing ;

Liang, Yu ;

Zhu, Fengyu ;

Zhang, Yingyin ;

Zhang, Xiuhong ;

Yuan, Quan ;

Li, Yang .

ONCOGENE, 2019, 38 (19) :3667-3680

[6] mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis [J].

Choe, Junho ;

Lin, Shuibin ;

Zhang, Wencai ;

Liu, Qi ;

Wang, Longfei ;

Ramirez-Moya, Julia ;

Du, Peng ;

Kim, Wantae ;

Tang, Shaojun ;

Sliz, Piotr ;

Santisteban, Pilar ;

George, Rani E. ;

Richards, William G. ;

Wong, Kwok-Kin ;

Locker, Nicolas ;

Slack, Frank J. ;

Gregory, Richard I. .

NATURE, 2018, 561 (7724) :556-+

[7] NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling [J].

Chowdhry, Sudhir ;

Zanca, Ciro ;

Rajkumar, Utkrisht ;

Koga, Tomoyuki ;

Diao, Yarui ;

Raviram, Ramya ;

Liu, Feng ;

Turner, Kristen ;

Yang, Huijun ;

Brunk, Elizabeth ;

Bi, Junfeng ;

Furnari, Frank ;

Bafna, Vineet ;

Ren, Bing ;

Mischel, Paul S. .

NATURE, 2019, 569 (7757) :570-+

[8] Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq [J].

Dominissini, Dan ;

Moshitch-Moshkovitz, Sharon ;

Schwartz, Schraga ;

Salmon-Divon, Mali ;

Ungar, Lior ;

Osenberg, Sivan ;

Cesarkas, Karen ;

Jacob-Hirsch, Jasmine ;

Amariglio, Ninette ;

Kupiec, Martin ;

Sorek, Rotem ;

Rechavi, Gideon .

NATURE, 2012, 485 (7397) :201-U84

[9] eIF3c: A potential therapeutic target for cancer [J].

Emmanuel, Rafi ;

Weinstein, Shiri ;

Landesman-Milo, Dalit ;

Peer, Dan .

CANCER LETTERS, 2013, 336 (01) :158-166

[10] Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells [J].

Han, Dali ;

Liu, Jun ;

Chen, Chuanyuan ;

Dong, Lihui ;

Liu, Yi ;

Chang, Renbao ;

Huang, Xiaona ;

Liu, Yuanyuan ;

Wang, Jianying ;

Dougherty, Urszula ;

Bissonnette, Marc B. ;

Shen, Bin ;

Weichselbaum, Ralph R. ;

Xu, Meng Michelle ;

He, Chuan .

NATURE, 2019, 566 (7743) :270-+

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