The RNA-binding protein SERBP1 functions as a novel oncogenic factor in glioblastoma by bridging cancer metabolism and epigenetic regulation.
Cancer metabolism
Epigenetic regulation
GBM
One carbon cycle
RNA-binding protein
SERBP1
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
06 08 2020
06 08 2020
Historique:
received:
23
03
2020
accepted:
22
07
2020
entrez:
9
8
2020
pubmed:
9
8
2020
medline:
9
7
2021
Statut:
epublish
Résumé
RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in RBP expression and function are often observed in cancer and influence critical pathways implicated in tumor initiation and growth. Identification and characterization of oncogenic RBPs and their regulatory networks provide new opportunities for targeted therapy. We identify the RNA-binding protein SERBP1 as a novel regulator of glioblastoma (GBM) development. High SERBP1 expression is prevalent in GBMs and correlates with poor patient survival and poor response to chemo- and radiotherapy. SERBP1 knockdown causes delay in tumor growth and impacts cancer-relevant phenotypes in GBM and glioma stem cell lines. RNAcompete identifies a GC-rich region as SERBP1-binding motif; subsequent genomic and functional analyses establish SERBP1 regulation role in metabolic routes preferentially used by cancer cells. An important consequence of these functions is SERBP1 impact on methionine production. SERBP1 knockdown decreases methionine levels causing a subsequent reduction in histone methylation as shown for H3K27me3 and upregulation of genes associated with neurogenesis, neuronal differentiation, and function. Further analysis demonstrates that several of these genes are downregulated in GBM, potentially through epigenetic silencing as indicated by the presence of H3K27me3 sites. SERBP1 is the first example of an RNA-binding protein functioning as a central regulator of cancer metabolism and indirect modulator of epigenetic regulation in GBM. By bridging these two processes, SERBP1 enhances glioma stem cell phenotypes and contributes to GBM poorly differentiated state.
Sections du résumé
BACKGROUND
RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in RBP expression and function are often observed in cancer and influence critical pathways implicated in tumor initiation and growth. Identification and characterization of oncogenic RBPs and their regulatory networks provide new opportunities for targeted therapy.
RESULTS
We identify the RNA-binding protein SERBP1 as a novel regulator of glioblastoma (GBM) development. High SERBP1 expression is prevalent in GBMs and correlates with poor patient survival and poor response to chemo- and radiotherapy. SERBP1 knockdown causes delay in tumor growth and impacts cancer-relevant phenotypes in GBM and glioma stem cell lines. RNAcompete identifies a GC-rich region as SERBP1-binding motif; subsequent genomic and functional analyses establish SERBP1 regulation role in metabolic routes preferentially used by cancer cells. An important consequence of these functions is SERBP1 impact on methionine production. SERBP1 knockdown decreases methionine levels causing a subsequent reduction in histone methylation as shown for H3K27me3 and upregulation of genes associated with neurogenesis, neuronal differentiation, and function. Further analysis demonstrates that several of these genes are downregulated in GBM, potentially through epigenetic silencing as indicated by the presence of H3K27me3 sites.
CONCLUSIONS
SERBP1 is the first example of an RNA-binding protein functioning as a central regulator of cancer metabolism and indirect modulator of epigenetic regulation in GBM. By bridging these two processes, SERBP1 enhances glioma stem cell phenotypes and contributes to GBM poorly differentiated state.
Identifiants
pubmed: 32762776
doi: 10.1186/s13059-020-02115-y
pii: 10.1186/s13059-020-02115-y
pmc: PMC7412812
doi:
Substances chimiques
RNA-Binding Proteins
0
SERBP1 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
195Subventions
Organisme : NHGRI NIH HHS
ID : R01 HG006015
Pays : United States
Organisme : NIH HHS
ID : 2R01 HG006015
Pays : United States
Références
Biochim Biophys Acta. 2012 Nov-Dec;1819(11-12):1132-41
pubmed: 22819712
Anal Chim Acta. 2018 Jun 29;1011:68-76
pubmed: 29475487
Cancer Biol Ther. 2019;20(7):979-988
pubmed: 30991885
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Trends Cancer. 2017 Jul;3(7):506-528
pubmed: 28718405
Anal Chem. 2006 Jul 1;78(13):4281-90
pubmed: 16808434
Nature. 2014 Mar 27;507(7493):462-70
pubmed: 24670764
Trends Cell Biol. 2016 May;26(5):367-378
pubmed: 26827090
Cell Rep. 2016 Apr 5;15(1):197-209
pubmed: 27052170
Int J Mol Sci. 2014 Mar 12;15(3):4393-414
pubmed: 24625664
Front Oncol. 2018 Oct 16;8:448
pubmed: 30386738
Nat Commun. 2016 Feb 03;7:10354
pubmed: 26838601
Adv Sci (Weinh). 2019 Mar 25;6(10):1801862
pubmed: 31131187
Cell Physiol Biochem. 2018;47(1):344-355
pubmed: 29768256
Adv Exp Med Biol. 2019;1157:29-39
pubmed: 31342436
Tumour Biol. 2016 Sep;37(9):12843-12854
pubmed: 27449037
Hum Mutat. 2020 Feb;41(2):476-486
pubmed: 31692205
Cancer Res. 2018 May 15;78(10):2463-2474
pubmed: 29549165
Cell Biochem Funct. 2018 Aug;36(6):312-322
pubmed: 30039520
Cell Metab. 2016 Jan 12;23(1):27-47
pubmed: 26771115
Biotechniques. 2004 Oct;37(4):604, 606, 608-10
pubmed: 15517973
Int J Cancer. 2015 Feb 15;136(4):E39-50
pubmed: 25142862
Neurogenetics. 2019 Oct;20(4):209-213
pubmed: 31372774
Cancer Res. 2016 Apr 15;76(8):2465-77
pubmed: 26896279
PLoS One. 2009 Jul 08;4(7):e6182
pubmed: 19584931
Nucleic Acids Res. 2017 Jul 3;45(W1):W98-W102
pubmed: 28407145
Nat Commun. 2014;5:3128
pubmed: 24451681
Brain Res. 2016 Sep 15;1647:1-8
pubmed: 26972534
Methods. 2017 Apr 15;118-119:3-15
pubmed: 27956239
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
Mol Cell. 2016 Jan 21;61(2):210-21
pubmed: 26774282
Neuron. 1996 Mar;16(3):675-86
pubmed: 8785064
Nat Neurosci. 2006 Oct;9(10):1294-301
pubmed: 16980967
Acta Neuropathol. 2012 Jul;124(1):83-97
pubmed: 22249620
Am J Hum Genet. 2019 Nov 7;105(5):1048-1056
pubmed: 31668703
Genome Biol. 2014;15(12):550
pubmed: 25516281
Nat Biotechnol. 2016 May;34(5):525-7
pubmed: 27043002
Nat Protoc. 2006;1(1):241-5
pubmed: 17406239
Nat Rev Clin Oncol. 2017 Jan;14(1):11-31
pubmed: 27141887
Biomed Res Int. 2015;2015:654765
pubmed: 26697491
Life Sci. 2019 Oct 1;234:116781
pubmed: 31430455
Nucleic Acids Res. 2010 Jan;38(Database issue):D204-10
pubmed: 20015972
Aging Cell. 2019 Dec;18(6):e13034
pubmed: 31460700
Stem Cells. 2016 Jan;34(1):220-32
pubmed: 26369286
Nat Rev Genet. 2014 Dec;15(12):829-45
pubmed: 25365966
Trends Endocrinol Metab. 2018 Sep;29(9):626-637
pubmed: 30001904
Mol Cell Biol. 2015 Sep 1;35(17):2965-78
pubmed: 26100017
Nat Rev Cancer. 2018 Nov;18(11):681-695
pubmed: 30181570
Mol Cancer. 2008 Jan 25;7:14
pubmed: 18221502
J Exp Clin Cancer Res. 2019 Feb 4;38(1):50
pubmed: 30717766
Nature. 2013 Jul 11;499(7457):172-7
pubmed: 23846655
Nat Genet. 2011 Jul 31;43(9):869-74
pubmed: 21804546
Nucleic Acids Res. 2007 Jan;35(Database issue):D521-6
pubmed: 17202168
PLoS One. 2013 May 30;8(5):e64140
pubmed: 23737970
Annu Rev Nutr. 2010 Aug 21;30:57-81
pubmed: 20645850
Gynecol Oncol. 2007 Nov;107(2):266-73
pubmed: 17698176
Int J Oncol. 2017 Aug;51(2):702-714
pubmed: 28656234
Cell. 2015 Sep 10;162(6):1217-28
pubmed: 26321681
PLoS One. 2011;6(7):e21800
pubmed: 21789182
J Neurooncol. 2013 Feb;111(3):245-55
pubmed: 23229761
Front Neurosci. 2019 Mar 19;13:243
pubmed: 30941009
F1000Res. 2015 Dec 30;4:1521
pubmed: 26925227
Neuro Oncol. 2017 Jan;19(1):139-141
pubmed: 28031383
Nat Genet. 2013 Jun;45(6):580-5
pubmed: 23715323
Nat Rev Cancer. 2013 Aug;13(8):572-83
pubmed: 23822983
Oncol Rep. 2016 Dec;36(6):3131-3138
pubmed: 27748938
Oncotarget. 2018 Feb 15;9(21):15451-15463
pubmed: 29643985
Proc Natl Acad Sci U S A. 2013 May 21;110(21):8644-9
pubmed: 23650391
Clin Cancer Res. 2016 Jul 15;22(14):3513-23
pubmed: 26936918
Cell Signal. 2017 Jul;35:256-263
pubmed: 28267599
Oncotarget. 2017 Jun 27;8(40):67567-67591
pubmed: 28978054
Drug Discov Today. 2019 Jan;24(1):179-188
pubmed: 30031878
Nucleic Acids Res. 2019 Jan 8;47(D1):D607-D613
pubmed: 30476243
Sci Rep. 2017 Jun 14;7(1):3455
pubmed: 28615704
Proc Natl Acad Sci U S A. 2018 Mar 20;115(12):E2734-E2741
pubmed: 29507191
Nat Biotechnol. 2009 Jul;27(7):667-70
pubmed: 19561594
Cell Rep. 2016 Jun 21;15(12):2692-704
pubmed: 27292631
Nucleic Acids Res. 2019 Jan 8;47(D1):D766-D773
pubmed: 30357393
Cancer Treat Rev. 2012 Oct;38(6):726-36
pubmed: 22342103
Acta Biochim Biophys Sin (Shanghai). 2017 May 1;49(5):383-391
pubmed: 28369267
Cell Physiol Biochem. 2016;39(1):395-406
pubmed: 27372650
Elife. 2018 Oct 24;7:
pubmed: 30355441
Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15281-6
pubmed: 18829439
Nature. 2008 Oct 23;455(7216):1061-8
pubmed: 18772890
Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7
pubmed: 27141961
Br J Cancer. 2017 Jun 6;116(12):1499-1504
pubmed: 28472819
Future Med Chem. 2012 Sep;4(13):1689-700
pubmed: 22924507
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Oncogene. 2018 Mar;37(12):1637-1653
pubmed: 29335519
J Proteomics. 2015 Sep 8;127(Pt A):61-70
pubmed: 25982388
Trends Cell Biol. 2011 Apr;21(4):228-37
pubmed: 21232958
Front Cell Dev Biol. 2017 Apr 26;5:43
pubmed: 28491867
J Transl Med. 2019 Jun 6;17(1):190
pubmed: 31171023
Acta Neuropathol. 2016 Jun;131(6):803-20
pubmed: 27157931
Nucleic Acids Res. 2015 Jul 27;43(13):6321-33
pubmed: 26068472
Annu Rev Neurosci. 2002;25:315-38
pubmed: 12052912
RNA Biol. 2018;15(11):1420-1432
pubmed: 30362859