METTL3-STAT5B interaction facilitates the co-transcriptional m6A modification of mRNA to promote breast tumorigenesis

被引:5
作者
Bhattarai, Poshan Yugal [1 ]
Kim, Garam [1 ]
Lim, Sung-Chul [2 ]
Choi, Hong Seok [1 ]
机构
[1] Chosun Univ, Res Inst Pharmaceut Sci, Coll Pharm, Gwangju 61452, South Korea
[2] Chosun Univ, Sch Med, Dept Pathol, Gwangju 61452, South Korea
基金
新加坡国家研究基金会;
关键词
Epitranscriptomic regulation; STAT5B activation; CTD phosphorylation; m 6 A modification; Breast tumorigenesis; TRANSLATION; METHYLATION; REVEALS; DOMAIN; STAT5;
D O I
10.1016/j.canlet.2024.217215
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Enhanced expression of methyltransferase-like 3 (METTL3) promotes the m6A modification of specific mRNAs, contributing to breast tumorigenesis. While the mRNA substrates targeted by METTL3 are well characterized, the factors dictating the selection of these specific mRNA remain elusive. This study aimed to examine the regulatory role of the transcription factor STAT5B in METTL3-induced m6A modification. METTL3 specifically interacts with STAT5B in response to mitogenic stimulation by epidermal growth factor (EGF). Chromatin immunoprecipitation and CRISPR/Cas9 mutagenesis showed that STAT5B recruits METTL3 to gene promoters like CCND1, where METTL3 interacts with RPB1, dependent on CDK9-mediated RPB1 (Ser2) phosphorylation during transcription elongation. Inhibition and depletion of either STAT5B or CDK9 prevented the EGF-induced m6A modification of CCND1. The translation efficiency of CCND1 was increased following m6A modification, thereby increasing cell proliferation. STAT5B facilitated METTL3-induced tumor formation by increasing CCND1 expression in an orthotopic mouse model. In clinical context, a positive correlation was observed between pSTAT5B and METTL3 expression in high-grade breast tumors. This study elucidates a novel mechanism that underlies the specificity of m6A modification in breast cancer cells, thereby underscoring its potential therapeutic value.
引用
收藏
页数:15
相关论文
共 50 条
[1]   METTL3 regulates breast cancer-associated alternative splicing switches [J].
Achour, Cyrinne ;
Bhattarai, Devi Prasad ;
Groza, Paula ;
Roman, angel-Carlos ;
Aguilo, Francesca .
ONCOGENE, 2023, 42 (12) :911-925
[2]   STAT proteins: a kaleidoscope of canonical and non-canonical functions in immunity and cancer [J].
Awasthi, Nagendra ;
Liongue, Clifford ;
Ward, Alister C. .
JOURNAL OF HEMATOLOGY & ONCOLOGY, 2021, 14 (01)
[3]   Role of N6-Methyladenosine (m6A) RNA Modification in Multiple Myeloma [J].
Bach, Christian ;
Leffler, Magdalena ;
Flamann, Cindy ;
Kronke, Jan ;
Mougiakakos, Dimitrios ;
Mackensen, Andreas ;
Bruns, Heiko .
BLOOD, 2018, 132
[4]   Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control [J].
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 .
NATURE, 2017, 552 (7683) :126-+
[5]   The SMAD2/3 interactome reveals that TGFβ controls m6A mRNA methylation in pluripotency [J].
Bertero, Alessandro ;
Brown, Stephanie ;
Madrigal, Pedro ;
Osnato, Anna ;
Ortmann, Daniel ;
Yiangou, Loukia ;
Kadiwala, Juned ;
Hubner, Nina C. ;
de los Mozos, Igor Ruiz ;
Sadee, Christoph ;
Lenaerts, An-Sofie ;
Nakanoh, Shota ;
Grandy, Rodrigo ;
Farnell, Edward ;
Ule, Jernej ;
Stunnenberg, Hendrik G. ;
Mendjan, Sasha ;
Vallier, Ludovic .
NATURE, 2018, 555 (7695) :256-+
[6]   METTL3 stabilization by PIN1 promotes breast tumorigenesis via enhanced m6A-dependent translation [J].
Bhattarai, Poshan Yugal ;
Kim, Garam ;
Lim, Sung-Chul ;
Mariappan, Ramesh ;
Ohn, Takbum ;
Choi, Hong Seok .
ONCOGENE, 2023, 42 (13) :1010-1023
[7]   METTL3 induces PLX4032 resistance in melanoma by promoting m6A-dependent EGFR translation [J].
Bhattarai, Poshan Yugal ;
Kim, Garam ;
Poudel, Muna ;
Lim, Sung-Chul ;
Choi, Hong Seok .
CANCER LETTERS, 2021, 522 :44-56
[8]   RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2 [J].
Chen, Mengnuo ;
Wei, Lai ;
Law, Cheuk-Ting ;
Tsang, Felice Ho-Ching ;
Shen, Jialing ;
Cheng, Carol Lai-Hung ;
Tsang, Long-Hin ;
Ho, Daniel Wai-Hung ;
Chiu, David Kung-Chun ;
Lee, Joyce Man-Fong ;
Wong, Carmen Chak-Lui ;
Ng, Irene Oi-Lin ;
Wong, Chun-Ming .
HEPATOLOGY, 2018, 67 (06) :2254-2270
[9]   Stat5a is tyrosine phosphorylated and nuclear localized in a high proportion of human breast cancers [J].
Cotarla, I ;
Ren, SX ;
Zhang, Y ;
Gehan, E ;
Singh, B ;
Furth, PA .
INTERNATIONAL JOURNAL OF CANCER, 2004, 108 (05) :665-671
[10]   The comprehensive interactomes of human adenosine RNA methyltransferases and demethylases reveal distinct functional and regulatory features [J].
Covelo-Molares, Helena ;
Obrdlik, Ales ;
Postulkova, Ivana ;
Dohnalkova, Michaela ;
Gregorova, Pavlina ;
Ganji, Ranjani ;
Potesil, David ;
Gawriyski, Lisa ;
Varjosalo, Markku ;
Vanacova, Stepanka .
NUCLEIC ACIDS RESEARCH, 2021, 49 (19) :10895-10910