N6-methyladenosine-modifying enzymes are deregulated in multiple myeloma

Year 2020, , 18 - 23, 26.02.2020

Dilara Akçora Yıldız

https://doi.org/10.18663/tjcl.489326

Abstract

Aim: N6-methyladenosine
(m6A) mRNA modification plays essential roles in various cellular processes
including regulation of gene expression. However, its role in Multiple Myeloma
(MM) biology remains largely unknown. Therefore, the aim of this study is to
investigate the expression levels of m6A-regulating enzymes in MM.

Material and Methods:
The expression of
m6A-regulating enzymes was investigated in monoclonal gammopathy of
undetermined significance (MGUS), smouldering MM (SMM), MM and in their normal
counterparts using publicly available Gene Expression Omnibus datasets, GSE6477
and GSE47552.

Results: By analyzing GEO
DataSets GSE6477 and GSE47552, the expression levels of METTL3, METTL14 and FTO were found to be downregulated
in MM, whereas
no significant change was found for WTAP, ALKBH5, YTHDF1 and YTHDF2. YTHDF3
expression showed a reduction in MM based on GSE6477 data.

Conclusion: The expression of
m6A-modifying genes is deregulated in MM plasma cells compared to normal plasma
cells. Altered expression of m6A-modifying genes seems to play a role in the
promotion of MM.

Keywords

Multiple myeloma, epitranscriptome, m6A, gene expression, METTL3, FTO

Multipl miyelomda N6-metiladenozin modifiye edici enzimlerin düzensizliği

Abstract

Amaç:
N6-metiladenozin (m6A) mRNA modifikasyonu, gen ekspresyonunun düzenlenmesi
dahil olmak üzere çeşitli hücresel işlemlerde önemli rol oynamaktadır. Bununla
birlikte, Multipl Miyelom (MM) biyolojisindeki rolü büyük ölçüde
bilinmemektedir. Bu nedenle, bu çalışmanın amacı MM'da m6A düzenleyici
enzimlerin ekspresyon düzeylerini araştırmaktır.

Gereç
ve Yöntemler: M6A düzenleyici enzimlerin ekspresyonu
kamuya açık Gene Expression Omnibus veri kümeleri GSE6477 ve GSE47552
kullanılarak, anlamı belirsiz monoklonal gamopati (MGUS), smouldering MM (SMM),
MM ve normal muadillerinde araştırılmıştır.

Bulgular:
GEO
data setleri GSE6477 ve GSE47552 analiz edilerek, METTL3, METTL14 ve FTO
ekspresyon seviyelerinin MM'da downregüle olduğu bulunurken WTAP, ALKBH5,
YTHDF1 ve YTHDF2 için anlamlı bir değişiklik bulunmadı. YTHDF3 ifadesi, GSE6477
verisine dayalı olarak MM'de bir azalma gösterdi.

Tartışma:
M6A değiştirici genlerin ifadesi, normal plazma hücrelerine kıyasla MM plazma
hücrelerinde deregüle edildiği bulunmuştur. M6A'nın modifiye edici genlerinin
değişmiş ifadesi, MM'nın oluşumunda rol oynar gibi görünmektedir.

Keywords

Multipl miyelom, epitranskriptom, m6A, gen ekpresyonu, METTL3, FTO

References

• 1- Kumar SK, Callander NS, Alsina M et al. Multiple Myeloma, Version 3. 2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2017; 15: 230-69.
• 2- Moreau P, San Miguel J, Sonneveld P et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28(suppl_4): iv52-iv61.
• 3- Nakaya A, Fujita S, Satake A et al. Impact of CRAB Symptoms in Survival of Patients with Symptomatic Myeloma in Novel Agent Era. Hematol Rep 2017; 9: 6887.
• 4- Engel M, Chen A. The emerging role of mRNA methylation in normal and pathological behavior. Genes Brain Behav 2018; 17: e12428.
• 5- Machnicka MA, Milanowska K, Osman Oglou O et al. MODOMICS: a database of RNA modification pathways– 2013 update. Nucleic Acids Res 2013; 41, D262–D267.
• 6- Li X, Xiong X, Yi C. Epitranscriptome sequencing technologies: decoding RNA modifications. Nat Methods 2016; 14: 23-31.
• 7- Maity A, Das B. N6-methyladenosine modification in mRNA: machinery, function and implications for health and diseases. FEBS J 2016; 283(9): 1607-30.
• 8- Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 2012; 485: 201–06.
• 9- Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR. Comprehensive analysis of mRNA methylation reveals enrichment in 3ʹ UTRs and near stop codons. Cell 2012; 149: 1635–1646.
• 10- Sun WJ, Li JH, Liu S, Wu J, Zhou H, Qu LH, et al. RMBase: a resource for decoding the landscape of RNA modifications from high-throughput sequencing data. Nucleic Acids Res 2016; 44: D259–D265.
• 11- Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA 1997; 3, 1233–47.
• 12- Liu J, Yue Y, Han D, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol 2014; 10: 93–95.
• 13- Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res 2014; 24: 177–89.
• 14- Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol 2017; 18: 31-42.
• 15- Yue Y, Liu J, He C. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev 2015; 29: 1343–55.
• 16- Pan Y, Ma P, Liu Y, Li W, Shu Y. Multiple functions of m(6)A RNA methylation in cancer. J Hematol Oncol 2018; 11: 48.
• 17- Chng WJ, Kumar S, Vanwier S et al. Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling. Cancer Res 2007; 67: 2982-89.
• 18- López-Corral L, Corchete LA, Sarasquete ME, et al. Transcriptome analysis reveals molecular profiles associated with evolving steps of monoclonal gammopathies. Haematologica 2014; 99: 1365-72.
• 19- Sibbritt T, Patel HR, Preiss T. Mapping and significance of the mRNA methylome. Wiley Interdiscip Rev RNA 2013; 4: 397–422.
• 20- Vu LP, Pickering BF, Cheng Y et al. The N(6)-methyladenosine (m(6)A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med 2017; 23: 1369-76.
• 21- Cui Q, Shi H, Ye P, Li L, Qu Q, Sun G et al. m(6)A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells. Cell Rep 2017; 18: 2622-34.
• 22- Bansal H, Yihua Q, Iyer SP, Ganapathy S, Proia DA, Proia D et al. WTAP is a novel oncogenic protein in acute myeloid leukemia. Leukemia 2014; 28: 1171–74.
• 23- Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y et al. R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling. Cell 2018; 172: 90–105.e23.
• 24- Zhang S, Zhao BS, Zhou A et al. m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell 2017; 31: 591–606.
• 25- Chen J, Sun Y, Xu X et al. YTH domain family 2 orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells. Cell Cycle 2017; 16: 2259–71.