The pancancer overexpressed NFYC Antisense 1 controls cell cycle mitotic progression through in cis and in trans modes of action.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
11 Mar 2024
11 Mar 2024
Historique:
received:
09
01
2024
accepted:
23
02
2024
revised:
20
02
2024
medline:
12
3
2024
pubmed:
12
3
2024
entrez:
12
3
2024
Statut:
epublish
Résumé
Antisense RNAs (asRNAs) represent an underappreciated yet crucial layer of gene expression regulation. Generally thought to modulate their sense genes in cis through sequence complementarity or their act of transcription, asRNAs can also regulate different molecular targets in trans, in the nucleus or in the cytoplasm. Here, we performed an in-depth molecular characterization of NFYC Antisense 1 (NFYC-AS1), the asRNA transcribed head-to-head to NFYC subunit of the proliferation-associated NF-Y transcription factor. Our results show that NFYC-AS1 is a prevalently nuclear asRNA peaking early in the cell cycle. Comparative genomics suggests a narrow phylogenetic distribution, with a probable origin in the common ancestor of mammalian lineages. NFYC-AS1 is overexpressed pancancer, preferentially in association with RB1 mutations. Knockdown of NFYC-AS1 by antisense oligonucleotides impairs cell growth in lung squamous cell carcinoma and small cell lung cancer cells, a phenotype recapitulated by CRISPR/Cas9-deletion of its transcription start site. Surprisingly, expression of the sense gene is affected only when endogenous transcription of NFYC-AS1 is manipulated. This suggests that regulation of cell proliferation is at least in part independent of the in cis transcription-mediated effect on NFYC and is possibly exerted by RNA-dependent in trans effects converging on the regulation of G2/M cell cycle phase genes. Accordingly, NFYC-AS1-depleted cells are stuck in mitosis, indicating defects in mitotic progression. Overall, NFYC-AS1 emerged as a cell cycle-regulating asRNA with dual action, holding therapeutic potential in different cancer types, including the very aggressive RB1-mutated tumors.
Identifiants
pubmed: 38467619
doi: 10.1038/s41419-024-06576-y
pii: 10.1038/s41419-024-06576-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
206Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : IG 2020 - ID. 24325
Informations de copyright
© 2024. The Author(s).
Références
Amaral P, Carbonell-Sala S, De La Vega FM, Faial T, Frankish A, Gingeras T, et al. The status of the human gene catalogue. Nature. 2023;622:41–7.
pubmed: 37794265
doi: 10.1038/s41586-023-06490-x
Frankish A, Carbonell-Sala S, Diekhans M, Jungreis I, Loveland JE, Mudge JM, et al. GENCODE: reference annotation for the human and mouse genomes in 2023. Nucleic Acids Res. 2023;51:D942–9.
pubmed: 36420896
doi: 10.1093/nar/gkac1071
Pagani G, Pandini C, Gandellini P. Navigating the multiverse of antisense RNAs: The transcription- and RNA-dependent dimension. Non-Cod RNA. 2022;8:74.
doi: 10.3390/ncrna8060074
Wery M, Gautier C, Descrimes M, Yoda M, Vennin-Rendos H, Migeot V, et al. Native elongating transcript sequencing reveals global anti-correlation between sense and antisense nascent transcription in fission yeast. RNA. 2018;24:196–208.
pubmed: 29114019
pmcid: 5769747
doi: 10.1261/rna.063446.117
Gil N, Ulitsky I. Regulation of gene expression by cis-acting long non-coding RNAs. Nat Rev Genet. 2020;21:102–17.
pubmed: 31729473
doi: 10.1038/s41576-019-0184-5
Pelechano V, Steinmetz LM. Gene regulation by antisense transcription. Nat Rev Genet. 2013;14:880–93.
pubmed: 24217315
doi: 10.1038/nrg3594
Zucchelli S, Cotella D, Takahashi H, Carrieri C, Cimatti L, Fasolo F, et al. SINEUPs: A new class of natural and synthetic antisense long non-coding RNAs that activate translation. RNA Biol. 2015;12:771–9.
pubmed: 26259533
pmcid: 4615742
doi: 10.1080/15476286.2015.1060395
Rey F, Pandini C, Messa L, Launi R, Barzaghini B, Zangaglia R, et al. α-Synuclein antisense transcript SNCA-AS1 regulates synapses- and aging-related genes suggesting its implication in Parkinson’s disease. Aging Cell. 2021;20:e13504.
pubmed: 34799977
pmcid: 8672788
doi: 10.1111/acel.13504
Rey F, Maghraby E, Messa L, Esposito L, Barzaghini B, Pandini C, et al. Identification of a novel pathway in sporadic Amyotrophic Lateral Sclerosis mediated by the long non-coding RNA ZEB1-AS1. Neurobiol Dis. 2023;178:106030.
pubmed: 36736597
doi: 10.1016/j.nbd.2023.106030
Cipriano A, Macino M, Buonaiuto G, Santini T, Biferali B, Peruzzi G, et al. Epigenetic regulation of Wnt7b expression by the cis-acting long noncoding RNA Lnc-Rewind in muscle stem cells. Lee JT, Struhl K, Khalil AS, editors. eLife. 2021 Jan 12;10:e54782.
Zhao S, Zhang X, Chen S, Zhang S. Natural antisense transcripts in the biological hallmarks of cancer: powerful regulators hidden in the dark. J Exp Clin Cancer Res. 2020;39:187.
pubmed: 32928281
pmcid: 7490906
doi: 10.1186/s13046-020-01700-0
Balbin OA, Malik R, Dhanasekaran SM, Prensner JR, Cao X, Wu YM, et al. The landscape of antisense gene expression in human cancers. Genome Res. 2015;25:1068–79.
pubmed: 26063736
pmcid: 4484389
doi: 10.1101/gr.180596.114
Mercer TR, Munro T, Mattick JS. The potential of long noncoding RNA therapies. Trends Pharm Sci. 2022;43:269–80.
pubmed: 35153075
doi: 10.1016/j.tips.2022.01.008
Tassinari M, Richter SN, Gandellini P. Biological relevance and therapeutic potential of G-quadruplex structures in the human noncoding transcriptome. Nucleic Acids Res. 2021;49:3617–33.
pubmed: 33721024
pmcid: 8053107
doi: 10.1093/nar/gkab127
Warner KD, Hajdin CE, Weeks KM. Principles for targeting RNA with drug-like small molecules. Nat Rev Drug Discov. 2018;17:547–58.
pubmed: 29977051
pmcid: 6420209
doi: 10.1038/nrd.2018.93
Khorkova O, Stahl J, Joji A, Volmar CH, Zeier Z, Wahlestedt C. Natural antisense transcripts as drug targets. Front Mol Biosci. 2022;9:978375.
pubmed: 36250017
pmcid: 9563854
doi: 10.3389/fmolb.2022.978375
Dolfini D, Gatta R, Mantovani R. NF-Y and the transcriptional activation of CCAAT promoters. Crit Rev Biochem Mol Biol. 2012;47:29–49.
pubmed: 22050321
doi: 10.3109/10409238.2011.628970
Gurtner A, Manni I, Piaggio G. NF-Y in cancer: Impact on cell transformation of a gene essential for proliferation. Biochim Biophys Acta BBA - Gene Regul Mech. 2017;1860:604–16.
doi: 10.1016/j.bbagrm.2016.12.005
Song Y, Du J, Lu P, Zou Q, Zeng S, Liu M, et al. LncRNA NFYC-AS1 promotes the development of lung adenocarcinomas through autophagy, apoptosis, and MET/c-Myc oncogenic proteins. Ann Transl Med. 2021;9:1621.
pubmed: 34926665
pmcid: 8640918
doi: 10.21037/atm-21-4995
Tong F, Xu L, Xu S, Zhang M. Identification of an autophagy-related 12-lncRNA signature and evaluation of NFYC-AS1 as a pro-cancer factor in lung adenocarcinoma. Front Genet. 2022;13:834935.
pubmed: 36105077
pmcid: 9466988
doi: 10.3389/fgene.2022.834935
Weinstein JN, Collisson EA, Mills GB, Shaw KRM, Ozenberger BA, Ellrott K, et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet. 2013;45:1113–20.
pubmed: 24071849
pmcid: 3919969
doi: 10.1038/ng.2764
Giacinti C, Giordano A. RB and cell cycle progression. Oncogene. 2006;25:5220–7.
pubmed: 16936740
doi: 10.1038/sj.onc.1209615
Wilkerson MD, Yin X, Hoadley KA, Liu Y, Hayward MC, Cabanski CR, et al. Lung squamous cell carcinoma mRNA expression subtypes are reproducible, clinically important and correspond to different normal cell types. Clin Cancer Res. 2010;16:4864–75.
pubmed: 20643781
pmcid: 2953768
doi: 10.1158/1078-0432.CCR-10-0199
George J, Lim JS, Jang SJ, Cun Y, Ozretić L, Kong G, et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47–53.
pubmed: 26168399
pmcid: 4861069
doi: 10.1038/nature14664
Ireland AS, Micinski AM, Kastner DW, Guo B, Wait SJ, Spainhower KB, et al. MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate. Cancer Cell. 2020;38:60–78.e12.
pubmed: 32473656
pmcid: 7393942
doi: 10.1016/j.ccell.2020.05.001
Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 2012;483:603–7.
pubmed: 22460905
pmcid: 3320027
doi: 10.1038/nature11003
Sonkin D, Thomas A, Teicher BA Are neuroendocrine negative small cell lung cancer and large cell neuroendocrine carcinoma with WT RB1 two faces of the same entity? Lung Cancer Manag. 8:LMT13.
Lizio M, Harshbarger J, Shimoji H, Severin J, Kasukawa T, Sahin S, et al. Gateways to the FANTOM5 promoter level mammalian expression atlas. Genome Biol. 2015;16:22.
pubmed: 25723102
pmcid: 4310165
doi: 10.1186/s13059-014-0560-6
Herrmann CJ, Schmidt R, Kanitz A, Artimo P, Gruber AJ, Zavolan M. PolyASite 2.0: a consolidated atlas of polyadenylation sites from 3′ end sequencing. Nucleic Acids Res. 2020;48:D174–9.
pubmed: 31617559
Miller DM, Thomas SD, Islam A, Muench D, Sedoris K. c-Myc and cancer metabolism. Clin Cancer Res. 2012;18:5546–53.
pubmed: 23071356
pmcid: 3505847
doi: 10.1158/1078-0432.CCR-12-0977
Ceribelli M, Benatti P, Imbriano C, Mantovani R. NF-YC complexity is generated by dual promoters and alternative splicing. J Biol Chem. 2009;284:34189–200.
pubmed: 19690168
pmcid: 2797189
doi: 10.1074/jbc.M109.008417
Le Béguec C, Wucher V, Lagoutte L, Cadieu E, Botherel N, Hédan B, et al. Characterisation and functional predictions of canine long non-coding RNAs. Sci Rep. 2018;8:13444.
pubmed: 30194329
pmcid: 6128939
doi: 10.1038/s41598-018-31770-2
Oliver KR, Greene WK. Transposable elements: powerful facilitators of evolution. BioEssays. 2009;31:703–14.
pubmed: 19415638
doi: 10.1002/bies.200800219
Sauta E, Reggiani F, Torricelli F, Zanetti E, Tagliavini E, Santandrea G, et al. CSNK1A1, KDM2A, and LTB4R2 are new druggable vulnerabilities in lung cancer. Cancers. 2021;13:3477.
pubmed: 34298691
pmcid: 8305418
doi: 10.3390/cancers13143477
Oser MG, Fonseca R, Chakraborty AA, Brough R, Spektor A, Jennings RB, et al. Cells lacking the RB1 tumor suppressor gene are hyperdependent on Aurora B kinase for survival. Cancer Discov. 2019;9:230–47.
pubmed: 30373918
doi: 10.1158/2159-8290.CD-18-0389
Hu Q, Lu JF, Luo R, Sen S, Maity SN. Inhibition of CBF/NF-Y mediated transcription activation arrests cells at G2/M phase and suppresses expression of genes activated at G2/M phase of the cell cycle. Nucleic Acids Res. 2006;34:6272–85.
pubmed: 17098936
pmcid: 1693888
doi: 10.1093/nar/gkl801
Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S, et al. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45:580–5.
doi: 10.1038/ng.2653
Morrish F, Neretti N, Sedivy JM, Hockenbery DM. The oncogene c-Myc coordinates regulation of metabolic networks to enable rapid cell cycle entry. Cell Cycle. 2008;7:1054–66.
pubmed: 18414044
doi: 10.4161/cc.7.8.5739
Hao Q, Zong X, Sun Q, Lin YC, Song YJ, Hashemikhabir S, et al. The S-phase-induced lncRNA SUNO1 promotes cell proliferation by controlling YAP1/Hippo signaling pathway. Davis RJ, Struhl K, editors. eLife. 2020 Oct 27;9:e55102.
Dhaka B, Zimmerli M, Hanhart D, Moser MB, Guillen-Ramirez H, Mishra S, et al. Functional identification of cis-regulatory long noncoding RNAs at controlled false discovery rates. Nucleic Acids Res. 2024 Feb 13:gkae075.
Stojic L, Lun ATL, Mascalchi P, Ernst C, Redmond AM, Mangei J, et al. A high-content RNAi screen reveals multiple roles for long noncoding RNAs in cell division. Nat Commun. 2020;11:1851.
pubmed: 32296040
pmcid: 7160116
doi: 10.1038/s41467-020-14978-7
Elguindy MM, Mendell JT. NORAD-induced Pumilio phase separation is required for genome stability. Nature. 2021;595:303–8.
pubmed: 34108682
pmcid: 8266761
doi: 10.1038/s41586-021-03633-w
Ali MM, Di Marco M, Mahale S, Jachimowicz D, Kosalai ST, Reischl S, et al. LY6K-AS lncRNA is a lung adenocarcinoma prognostic biomarker and regulator of mitotic progression. Oncogene. 2021;40:2463–78.
pubmed: 33674747
doi: 10.1038/s41388-021-01696-7
Fischer M, Schade AE, Branigan TB, Müller GA, DeCaprio JA. Coordinating gene expression during the cell cycle. Trends Biochem Sci. 2022;47:1009–22.
pubmed: 35835684
doi: 10.1016/j.tibs.2022.06.007
Jiang Z, Jones R, Liu JC, Deng T, Robinson T, Chung PED, et al. RB1 and p53 at the crossroad of EMT and triple-negative breast cancer. Cell Cycle. 2011;10:1563–70.
pubmed: 21502814
doi: 10.4161/cc.10.10.15703
Stojic L, Niemczyk M, Orjalo A, Ito Y, Ruijter AEM, Uribe-Lewis S, et al. Transcriptional silencing of long noncoding RNA GNG12-AS1 uncouples its transcriptional and product-related functions. Nat Commun. 2016;7:10406.
pubmed: 26832224
pmcid: 4740813
doi: 10.1038/ncomms10406
Boque-Sastre R, Soler M, Oliveira-Mateos C, Portela A, Moutinho C, Sayols S, et al. Head-to-head antisense transcription and R-loop formation promotes transcriptional activation. Proc Natl Acad Sci. 2015;112:5785–90.
pubmed: 25902512
pmcid: 4426458
doi: 10.1073/pnas.1421197112
Pan K, Xie Y. LncRNA FOXC2-AS1 enhances FOXC2 mRNA stability to promote colorectal cancer progression via activation of Ca2+-FAK signal pathway. Cell Death Dis. 2020;11:1–14.
doi: 10.1038/s41419-020-2633-7
Latos PA, Pauler FM, Koerner MV, Şenergin HB, Hudson QJ, Stocsits RR, et al. Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing. Science. 2012;338:1469–72.
pubmed: 23239737
doi: 10.1126/science.1228110
Wery M, Gautier C, Descrimes M, Yoda M, Migeot V, Hermand D, et al. Bases of antisense lncRNA-associated regulation of gene expression in fission yeast. PLOS Genet. 2018;14:e1007465.
pubmed: 29975684
pmcid: 6049938
doi: 10.1371/journal.pgen.1007465
Martens JA, Laprade L, Winston F. Intergenic transcription is required to repress the Saccharomyces cerevisiae SER3 gene. Nature. 2004;429:571–4.
pubmed: 15175754
doi: 10.1038/nature02538
Beucher A, Miguel-Escalada I, Balboa D, De Vas MG, Maestro MA, Garcia-Hurtado J, et al. The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A. Nat Cell Biol. 2022;24:1528–40.
pubmed: 36202974
pmcid: 9586874
doi: 10.1038/s41556-022-00996-8
Goyal A, Myacheva K, Groß M, Klingenberg M, Duran Arqué B, Diederichs S. Challenges of CRISPR/Cas9 applications for long non-coding RNA genes. Nucleic Acids Res. 2017;45:e12.
pubmed: 28180319
Belluti S, Semeghini V, Basile V, Rigillo G, Salsi V, Genovese F, et al. An autoregulatory loop controls the expression of the transcription factor NF-Y. Biochim Biophys Acta BBA - Gene Regul Mech. 2018;1861:509–18.
doi: 10.1016/j.bbagrm.2018.02.008
Johnson R, Guigó R. The RIDL hypothesis: transposable elements as functional domains of long noncoding RNAs. RNA. 2014;20:959–76.
pubmed: 24850885
pmcid: 4114693
doi: 10.1261/rna.044560.114
Profumo V, Forte B, Percio S, Rotundo F, Doldi V, Ferrari E, et al. LEADeR role of miR-205 host gene as long noncoding RNA in prostate basal cell differentiation. Nat Commun. 2019;10:307.
pubmed: 30659180
pmcid: 6338800
doi: 10.1038/s41467-018-08153-2
Bezzecchi E, Pagani G, Forte B, Percio S, Zaffaroni N, Dolfini D, et al. MIR205HG/LEADR long noncoding RNA binds to primed proximal regulatory regions in prostate basal cells through a triplex- and alu-mediated mechanism. Front Cell Dev Biol. 2022;10:909097.
pubmed: 35784469
pmcid: 9247157
doi: 10.3389/fcell.2022.909097
Puvvula PK, Desetty RD, Pineau P, Marchio A, Moon A, Dejean A, et al. Long noncoding RNA PANDA and scaffold-attachment-factor SAFA control senescence entry and exit. Nat Commun. 2014;5:5323.
pubmed: 25406515
doi: 10.1038/ncomms6323
Logotheti S, Marquardt S, Gupta SK, Richter C, Edelhäuser BAH, Engelmann D, et al. LncRNA-SLC16A1-AS1 induces metabolic reprogramming during Bladder Cancer progression as target and co-activator of E2F1. Theranostics. 2020;10:9620–43.
pubmed: 32863950
pmcid: 7449907
doi: 10.7150/thno.44176
Dolfini D, Zambelli F, Pedrazzoli M, Mantovani R, Pavesi G. A high definition look at the NF-Y regulome reveals genome-wide associations with selected transcription factors. Nucleic Acids Res. 2016;44:4684–702.
pubmed: 26896797
pmcid: 4889920
doi: 10.1093/nar/gkw096