MYC promotes cancer progression by modulating m6A modifications to suppress target gene translation

被引：29

作者：

Wu, Gongwei ^{[1
,2
]}

Suo, Caixia ^{[1
,3
]}

Yang, Ying ^{[4
]}

Shen, Shengqi ^{[2
]}

Sun, Linchong ^{[1
,3
]}

Li, Shi-Ting ^{[2
]}

Zhou, Yingli ^{[2
]}

Yang, Dongdong ^{[2
]}

Wang, Yan ^{[2
]}

Cai, Yongping ^{[5
]}

Wang, Nana ^{[5
]}

Zhang, Huafeng ^{[2
]}

Yang, Yun-Gui ^{[4
,6
,7
,8
]}

Cao, Jie ^{[1
,3
]}

Gao, Ping ^{[1
,2
,9
]}

机构：

[1] South China Univ Technol, Inst Life Sci, Sch Med, Guangzhou Peoples Hosp 1, Guangzhou, Peoples R China

[2] Univ Sci & Technol China, CAS Key Lab Innate Immun & Chron Dis, Innovat Ctr Cell Signaling Network, Sch Life Sci, Hefei, Anhui, Peoples R China

[3] South China Univ Technol, Sch Biomed Sci & Engn, Guangzhou Int Campus, Guangzhou, Peoples R China

[4] Chinese Acad Sci, Collaborat Innovat Ctr Genet & Dev, CAS Ctr Excellence Mol Cell Sci, Key Lab Genom & Precis Med,Beijing Inst Genom, Beijing, Peoples R China

[5] Anhui Med Univ, Sch Med, Dept Pathol, Hefei, Anhui, Peoples R China

[6] Univ Chinese Acad Sci, Beijing, Peoples R China

[7] China Natl Ctr Bioinformat, Beijing, Peoples R China

[8] Chinese Acad Sci, Inst Stem Cell & Regenerat, Beijing, Peoples R China

[9] Guangzhou Regenerat Med & Hlth Guangdong Lab, Guangzhou, Peoples R China

来源：

EMBO REPORTS | 2021年 / 22卷 / 03期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

ALKBH5; m(6)A; MYC; MYC-repressed genes; oncogenesis; C-MYC; RNA; EXPRESSION; TRANSCRIPTION; DEMETHYLASE; ACTIVATION; REPRESSION; METHYLTRANSFERASE; REARRANGEMENT; METHYLATION;

D O I：

10.15252/embr.202051519

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：

The MYC oncoprotein activates and represses gene expression in a transcription-dependent or transcription-independent manner. Modification of mRNA emerges as a key gene expression regulatory nexus. We sought to determine whether MYC alters mRNA modifications and report here that MYC promotes cancer progression by down-regulating N6-methyladenosine (m(6)A) preferentially in transcripts of a subset of MYC-repressed genes (MRGs). We find that MYC activates the expression of ALKBH5 and reduces m(6)A levels in the mRNA of the selected MRGs SPI1 and PHF12. We also show that MYC-regulated m(6)A controls the translation of MRG mRNA via the specific m(6)A reader YTHDF3. Finally, we find that inhibition of ALKBH5, or overexpression of SPI1 or PHF12, effectively suppresses the growth of MYC-deregulated B-cell lymphomas, both in vitro and in vivo. Our findings uncover a novel mechanism by which MYC suppresses gene expression by altering m(6)A modifications in selected MRG transcripts promotes cancer progression.

引用

页数：15

共 58 条

[1] Structure of human RNA N6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation
Aik, WeiShen
Scotti, John S.
Choi, Hwanho
Gong, Lingzhi
Demetriades, Marina
Schofield, Christopher J.
McDonough, Michael A.
[J]. NUCLEIC ACIDS RESEARCH, 2014, 42 (07) : 4741 - 4754
[2] Target gene-independent functions of MYC oncoproteins
Baluapuri, Apoorva
Wolf, Elmar
Eilers, Martin
[J]. NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2020, 21 (05) : 255 - 267
[3] MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation
Baluapuri, Apoorva
Hofstetter, Julia
Stankovic, Nevenka Dudvarski
Endres, Theresa
Bhandare, Pranjali
Vos, Seychelle Monique
Adhikari, Bikash
Schwarz, Jessica Denise
Narain, Ashwin
Vogt, Markus
Wang, Shuang-Yan
Duester, Robert
Jung, Lisa Anna
Vanselow, Jens Thorsten
Wiegering, Armin
Geyer, Matthias
Maric, Hans Michael
Gallant, Peter
Walz, Susanne
Schlosser, Andreas
Cramer, Patrick
Eilers, Martin
Wolf, Elmar
[J]. MOLECULAR CELL, 2019, 74 (04) : 674 - +
[4] WTAP is a novel oncogenic protein in acute myeloid leukemia
Bansal, H.
Yihua, Q.
Iyer, S. P.
Ganapathy, S.
Proia, D.
Penalva, L. O.
Uren, P. J.
Suresh, U.
Carew, J. S.
Karnad, A. B.
Weitman, S.
Tomlinson, G. E.
Rao, M. K.
Kornblau, S. M.
Bansal, S.
[J]. LEUKEMIA, 2014, 28 (05) : 1171 - 1174
[5] Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control
Barbieri, Isaia
Tzelepis, Konstantinos
Pandolfini, Luca
Shi, Junwei
Millan-Zambrano, Gonzalo
Robson, Samuel C.
Aspris, Demetrios
Migliori, Valentina
Bannister, Andrew J.
Han, Namshik
De Braekeleer, Etienne
Ponstingl, Hannes
Hendrick, Alan
Vakoc, Christopher R.
Vassiliou, George S.
Kouzarides, Tony
[J]. NATURE, 2017, 552 (7683) : 126 - +
[6] Rearrangement of MYC Is Associated With Poor Prognosis in Patients With Diffuse Large B-Cell Lymphoma Treated in the Era of Rituximab
Barrans, Sharon
Crouch, Simon
Smith, Alex
Turner, Kathryn
Owen, Roger
Patmore, Russell
Roman, Eve
Jack, Andrew
[J]. JOURNAL OF CLINICAL ONCOLOGY, 2010, 28 (20) : 3360 - 3365
[7] Readers of the m6A epitranscriptomic code
Berlivet, Soizik
Scutenaire, Jeremy
Deragon, Jean-Marc
Bousquet-Antonelli, Cecile
[J]. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS, 2019, 1862 (03): : 329 - 342
[8] Recent advances in dynamic m6A RNA modification
Cao, Guangchao
Li, Hua-Bing
Yin, Zhinan
Flavell, Richard A.
[J]. OPEN BIOLOGY, 2016, 6 (04):
[9] Molecular Classification of MYC-Driven B-Cell Lymphomas by Targeted Gene Expression Profiling of Fixed Biopsy Specimens
Carey, Christopher D.
Gusenleitner, Daniel
Chapuy, Bjoern
Kovach, Alexandra E.
Kluk, Michael J.
Sun, Heather H.
Crossland, Rachel E.
Bacon, Chris M.
Rand, Vikki
Dal Cin, Paola
Le, Long P.
Neuberg, Donna
Sohani, Aliyah R.
Shipp, Margaret A.
Monti, Stefano
Rodig, Scott J.
[J]. JOURNAL OF MOLECULAR DIAGNOSTICS, 2015, 17 (01) : 19 - 30
[10] c-Myc steers translation in lymphoma
Cargnello, Marie
Topisirovic, Ivan
[J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2019, 216 (07) : 1471 - 1473

← 1 2 3 4 5 6 →