Staufen1 controls mitochondrial metabolism via HIF2α in embryonal rhabdomyosarcoma and promotes tumorigenesis.
Embryonal rhabdomyosarcoma
Mitochondrial metabolism
OXPHOS
STAU1
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
17 Oct 2023
17 Oct 2023
Historique:
received:
20
05
2023
accepted:
18
09
2023
revised:
31
08
2023
medline:
23
10
2023
pubmed:
17
10
2023
entrez:
17
10
2023
Statut:
epublish
Résumé
Elevated mitochondrial metabolism promotes tumorigenesis of Embryonal Rhabdomyosarcomas (ERMS). Accordingly, targeting oxidative phosphorylation (OXPHOS) could represent a therapeutic strategy for ERMS. We previously demonstrated that genetic reduction of Staufen1 (STAU1) levels results in the inhibition of ERMS tumorigenicity. Here, we examined STAU1-mediated mechanisms in ERMS and focused on its potential involvement in regulating OXPHOS. We report the novel and differential role of STAU1 in mitochondrial metabolism in cancerous versus non-malignant skeletal muscle cells (NMSkMCs). Specifically, our data show that STAU1 depletion reduces OXPHOS and inhibits proliferation of ERMS cells. Our findings further reveal the binding of STAU1 to several OXPHOS mRNAs which affects their stability. Indeed, STAU1 depletion reduced the stability of OXPHOS mRNAs, causing inhibition of mitochondrial metabolism. In parallel, STAU1 depletion impacted negatively the HIF2α pathway which further modulates mitochondrial metabolism. Exogenous expression of HIF2α in STAU1-depleted cells reversed the mitochondrial inhibition and induced cell proliferation. However, opposite effects were observed in NMSkMCs. Altogether, these findings revealed the impact of STAU1 in the regulation of mitochondrial OXPHOS in cancer cells as well as its differential role in NMSkMCs. Overall, our results highlight the therapeutic potential of targeting STAU1 as a novel approach for inhibiting mitochondrial metabolism in ERMS.
Identifiants
pubmed: 37847286
doi: 10.1007/s00018-023-04969-4
pii: 10.1007/s00018-023-04969-4
doi:
Substances chimiques
Cytoskeletal Proteins
0
RNA, Messenger
0
STAU1 protein, human
0
RNA-Binding Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
328Subventions
Organisme : Canadian Cancer Research Society
ID : 24303
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
Références
Rudzinski ER, Anderson JR, Chi Y-Y et al (2017) Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer. https://doi.org/10.1002/pbc.26645
doi: 10.1002/pbc.26645
pubmed: 28521080
pmcid: 5647228
Wang C (2012) Childhood rhabdomyosarcoma: recent advances and prospective views. J Dent Res 91:341–350. https://doi.org/10.1177/0022034511421490
doi: 10.1177/0022034511421490
pubmed: 21917598
pmcid: 3310752
Hettmer S, Wagers AJ (2010) Muscling in: uncovering the origins of rhabdomyosarcoma. Nat Med 16:171–173. https://doi.org/10.1038/nm0210-171
doi: 10.1038/nm0210-171
pubmed: 20134473
Sarkar D, Ray S, Saha M et al (2012) Alveolar rhabdomyosarcoma with multiple distal metastases. A case report and review of literature. BMJ Case Rep. https://doi.org/10.1136/bcr-2012-006523
doi: 10.1136/bcr-2012-006523
pubmed: 23076702
pmcid: 4544940
Galili N, Davis RJ, Fredericks WJ et al (1993) Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet 5:230–235. https://doi.org/10.1038/ng1193-230
doi: 10.1038/ng1193-230
pubmed: 8275086
Skapek SX, Ferrari A, Gupta AA et al (2019) Rhabdomyosarcoma. Nat Rev Dis Prim 5:1. https://doi.org/10.1038/s41572-018-0051-2
doi: 10.1038/s41572-018-0051-2
pubmed: 30617281
Oberlin O, Rey A, Lyden E et al (2008) Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups. J Clin Oncol 26:2384–2389. https://doi.org/10.1200/JCO.2007.14.7207
doi: 10.1200/JCO.2007.14.7207
pubmed: 18467730
pmcid: 4558625
Chen X, Stewart E, Shelat AA et al (2013) Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell 24:710–724. https://doi.org/10.1016/j.ccr.2013.11.002
doi: 10.1016/j.ccr.2013.11.002
pubmed: 24332040
pmcid: 3904731
Solaini G, Baracca A, Lenaz G, Sgarbi G (2010) Hypoxia and mitochondrial oxidative metabolism. Biochim Biophys Acta 1797:1171–1177. https://doi.org/10.1016/j.bbabio.2010.02.011
doi: 10.1016/j.bbabio.2010.02.011
pubmed: 20153717
Chandel NS, Maltepe E, Goldwasser E et al (1998) Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA 95:11715–11720. https://doi.org/10.1073/pnas.95.20.11715
doi: 10.1073/pnas.95.20.11715
pubmed: 9751731
pmcid: 21706
Monti E, Fanzani A (2016) Uncovering metabolism in rhabdomyosarcoma. Cell Cycle 15:184–195. https://doi.org/10.1080/15384101.2015.1071746
doi: 10.1080/15384101.2015.1071746
pubmed: 26209235
Crawford Parks TE, Marcellus KA, Langill J et al (2017) Novel Roles for Staufen1 in Embryonal and Alveolar Rhabdomyosarcoma via c-myc-dependent and -independent events. Sci Rep 7:42342. https://doi.org/10.1038/srep42342
doi: 10.1038/srep42342
pubmed: 28211476
pmcid: 5314364
Almasi S, Parks TEC, Ravel-Chapuis A et al (2021) Differential regulation of autophagy by STAU1 in alveolar rhabdomyosarcoma and non-transformed skeletal muscle cells. Cell Oncol (Dordr) 44:851–870. https://doi.org/10.1007/s13402-021-00607-y
doi: 10.1007/s13402-021-00607-y
pubmed: 33899158
Almasi S, Jasmin BJ (2021) The multifunctional RNA-binding protein Staufen1: an emerging regulator of oncogenesis through its various roles in key cellular events. Cell Mol Life Sci 78:7145–7160. https://doi.org/10.1007/s00018-021-03965-w
doi: 10.1007/s00018-021-03965-w
pubmed: 34633481
pmcid: 8629789
Park E, Maquat LE (2013) Staufen-mediated mRNA decay. Wiley Interdiscip Rev RNA 4:423–435. https://doi.org/10.1002/wrna.1168
doi: 10.1002/wrna.1168
pubmed: 23681777
pmcid: 3711692
Gonzalez Quesada Y, Bonnet-Magnaval F, DesGroseillers L (2022) Phosphomimicry on STAU1 Serine 20 impairs STAU1 posttranscriptional functions and induces apoptosis in human transformed cells. Int J Mol Sci. https://doi.org/10.3390/ijms23137344
doi: 10.3390/ijms23137344
pubmed: 36232890
pmcid: 9569955
Gonzalez Quesada Y, DesGroseillers L (2022) A degradation motif in STAU1 defines a novel family of proteins involved in inflammation. Int J Mol Sci 23:11588. https://doi.org/10.3390/ijms231911588
doi: 10.3390/ijms231911588
pubmed: 36232890
pmcid: 9569955
Haimovich G, Medina DA, Causse SZ et al (2013) Gene expression is circular: factors for mRNA degradation also Foster mRNA synthesis. Cell 153:1000–1011. https://doi.org/10.1016/j.cell.2013.05.012
doi: 10.1016/j.cell.2013.05.012
pubmed: 23706738
Marcellus KA, Crawford Parks TE, Almasi S, Jasmin BJ (2021) Distinct roles for the RNA-binding protein Staufen1 in prostate cancer. BMC Cancer 21:120. https://doi.org/10.1186/s12885-021-07844-2
doi: 10.1186/s12885-021-07844-2
pubmed: 33541283
pmcid: 7863451
Paul S, Dansithong W, Figueroa KP et al (2021) Staufen1 in human neurodegeneration. Ann Neurol 89:1114–1128. https://doi.org/10.1002/ana.26069
doi: 10.1002/ana.26069
pubmed: 33745139
pmcid: 9724591
Damas ND, Marcatti M, Côme C et al (2016) SNHG5 promotes colorectal cancer cell survival by counteracting STAU1-mediated mRNA destabilization. Nat Commun 7:13875. https://doi.org/10.1038/ncomms13875
doi: 10.1038/ncomms13875
pubmed: 28004750
pmcid: 5192221
Bonnet-Magnaval F, Diallo LH, Brunchault V et al (2021) High level of Staufen1 expression confers longer recurrence free survival to non-small cell lung cancer patients by promoting THBS1 mRNA degradation. Int J Mol Sci 23:215. https://doi.org/10.3390/ijms23010215
doi: 10.3390/ijms23010215
pubmed: 35008641
pmcid: 8745428
Bonnet-Magnaval F, DesGroseillers L (2021) The Staufen1-dependent cell cycle regulon or how a misregulated RNA-binding protein leads to cancer. Biol Rev Camb Philos Soc 96:2192–2208. https://doi.org/10.1111/brv.12749
doi: 10.1111/brv.12749
pubmed: 34018319
Ghram M, Bonnet-Magnaval F, Hotea DI et al (2020) Staufen1 is essential for cell-cycle transitions and cell proliferation via the control of E2F1 expression. J Mol Biol 432:3881–3897. https://doi.org/10.1016/j.jmb.2020.04.016
doi: 10.1016/j.jmb.2020.04.016
pubmed: 32335035
Pantic B, Borgia D, Giunco S et al (2016) Reliable and versatile immortal muscle cell models from healthy and myotonic dystrophy type 1 primary human myoblasts. Exp Cell Res 342:39–51
doi: 10.1016/j.yexcr.2016.02.013
pubmed: 26905645
Hinson ARP, Jones R, Crose LES et al (2013) Human rhabdomyosarcoma cell lines for rhabdomyosarcoma research: utility and pitfalls. Front Oncol 3:183
doi: 10.3389/fonc.2013.00183
pubmed: 23882450
pmcid: 3713458
Klages N, Zufferey R, Trono D (2000) A stable system for the high-titer production of multiply attenuated lentiviral vectors. Mol Ther 2:170–176. https://doi.org/10.1006/mthe.2000.0103
doi: 10.1006/mthe.2000.0103
pubmed: 10947945
Perez-Riverol Y, Bai J, Bandla C et al (2022) The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res 50:D543–D552. https://doi.org/10.1093/nar/gkab1038
doi: 10.1093/nar/gkab1038
pubmed: 34723319
Gehlenborg N, Wong B (2012) Heat maps. Nat Methods 9:213–213. https://doi.org/10.1038/nmeth.1902
doi: 10.1038/nmeth.1902
pubmed: 27974286
Tang JX, Thompson K, Taylor RW, Oláhová M (2020) Mitochondrial OXPHOS biogenesis: co-regulation of protein synthesis, import, and assembly pathways. Int J Mol Sci 21:3820. https://doi.org/10.3390/ijms21113820
doi: 10.3390/ijms21113820
pubmed: 32481479
pmcid: 7312649
Park D, Lee S, Min K-T (2020) Techniques for investigating mitochondrial gene expression. BMB Rep 53:3–9. https://doi.org/10.5483/BMBRep.2020.53.1.272
doi: 10.5483/BMBRep.2020.53.1.272
pubmed: 31818361
pmcid: 6999826
Furic L, Maher-Laporte M, DesGroseillers L (2008) A genome-wide approach identifies distinct but overlapping subsets of cellular mRNAs associated with Staufen1- and Staufen2-containing ribonucleoprotein complexes. RNA 14:324–335. https://doi.org/10.1261/rna.720308
doi: 10.1261/rna.720308
pubmed: 18094122
pmcid: 2212254
Sugimoto Y, Vigilante A, Darbo E et al (2015) hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1. Nature 519:491–494. https://doi.org/10.1038/nature14280
doi: 10.1038/nature14280
pubmed: 25799984
pmcid: 4376666
Crawford Parks TE, Marcellus KA, Péladeau C et al (2020) Overexpression of Staufen1 in DM1 mouse skeletal muscle exacerbates dystrophic and atrophic features. Hum Mol Genet 29:2185–2199. https://doi.org/10.1093/hmg/ddaa111
doi: 10.1093/hmg/ddaa111
pubmed: 32504084
pmcid: 7399530
Gong C, Kim YK, Woeller CF et al (2009) SMD and NMD are competitive pathways that contribute to myogenesis: effects on PAX3 and myogenin mRNAs. Genes Dev 23:54–66. https://doi.org/10.1101/gad.1717309
doi: 10.1101/gad.1717309
pubmed: 19095803
pmcid: 2632170
Krämer A, Green J, Pollard J, Tugendreich S (2014) Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics 30:523–530. https://doi.org/10.1093/bioinformatics/btt703
doi: 10.1093/bioinformatics/btt703
pubmed: 24336805
Sharma LK, Lu J, Bai Y (2009) Mitochondrial respiratory complex I: structure, function and implication in human diseases. Curr Med Chem 16:1266–1277. https://doi.org/10.2174/092986709787846578
doi: 10.2174/092986709787846578
pubmed: 19355884
pmcid: 4706149
Chujo T, Ohira T, Sakaguchi Y et al (2012) LRPPRC/SLIRP suppresses PNPase-mediated mRNA decay and promotes polyadenylation in human mitochondria. Nucleic Acids Res 40:8033–8047. https://doi.org/10.1093/nar/gks506
doi: 10.1093/nar/gks506
pubmed: 22661577
pmcid: 3439899
Nagao A, Hino-Shigi N, Suzuki T (2008) Chapter 23 measuring mRNA decay in human mitochondria. Elsevier, Amsterdam, pp 489–499
Burslem GM, Kyle HF, Nelson A et al (2017) Hypoxia inducible factor (HIF) as a model for studying inhibition of protein-protein interactions. Chem Sci 8:4188–4202. https://doi.org/10.1039/c7sc00388a
doi: 10.1039/c7sc00388a
pubmed: 28878873
pmcid: 5576430
Orrenius S, Gogvadze V, Zhivotovsky B (2007) Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 47:143–183. https://doi.org/10.1146/annurev.pharmtox.47.120505.105122
doi: 10.1146/annurev.pharmtox.47.120505.105122
pubmed: 17029566
Bao X, Zhang J, Huang G et al (2021) The crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Cell Death Dis 12:215. https://doi.org/10.1038/s41419-021-03505-1
doi: 10.1038/s41419-021-03505-1
pubmed: 33637686
pmcid: 7910460
Kuhnt T, Pelz T, Qu X et al (2007) Mitochondrial OXPHOS Functions in R1H Rhabdomyosarcoma and Skeletal Muscles of the Rat. Neurochem Res 32:973–980. https://doi.org/10.1007/s11064-006-9254-0
doi: 10.1007/s11064-006-9254-0
pubmed: 17273927
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7:11–20. https://doi.org/10.1016/j.cmet.2007.10.002
doi: 10.1016/j.cmet.2007.10.002
pubmed: 18177721
Fell D, Athel C-B (1997) Understanding the control of metabolism. Portland Press, London
Alabduladhem TO, Bordoni B (2022) Physiology, Krebs Cycle
Fan TW, Kucia M, Jankowski K et al (2008) Rhabdomyosarcoma cells show an energy producing anabolic metabolic phenotype compared with primary myocytes. Mol Cancer 7:79. https://doi.org/10.1186/1476-4598-7-79
doi: 10.1186/1476-4598-7-79
pubmed: 18939998
pmcid: 2577687
Chiu HY, Loh AHP, Taneja R (2022) Mitochondrial calcium uptake regulates tumour progression in embryonal rhabdomyosarcoma. Cell Death Dis 13:419. https://doi.org/10.1038/s41419-022-04835-4
doi: 10.1038/s41419-022-04835-4
pubmed: 35490194
pmcid: 9056521
Heinicke U, Kupka J, Fichter I, Fulda S (2016) Critical role of mitochondria-mediated apoptosis for JNJ-26481585-induced antitumor activity in rhabdomyosarcoma. Oncogene 35:3729–3741. https://doi.org/10.1038/onc.2015.440
doi: 10.1038/onc.2015.440
pubmed: 26616861
Zhang M, Linardic CM, Kirsch DG (2013) RAS and ROS in Rhabdomyosarcoma. Cancer Cell 24:689–691. https://doi.org/10.1016/j.ccr.2013.11.015
doi: 10.1016/j.ccr.2013.11.015
pubmed: 24332036
pmcid: 3985483
Yang L, Kong D, He M et al (2020) MiR-7 mediates mitochondrial impairment to trigger apoptosis and necroptosis in Rhabdomyosarcoma. Biochim Biophys Acta - Mol Cell Res 1867:118826. https://doi.org/10.1016/j.bbamcr.2020.118826
doi: 10.1016/j.bbamcr.2020.118826
pubmed: 32810522
Almasi S, Kennedy BE, El-Aghil M et al (2018) TRPM2 channel-mediated regulation of autophagy maintains mitochondrial function and promotes gastric cancer cell survival via the JNK-signaling pathway. J Biol Chem 293:3637–3650. https://doi.org/10.1074/jbc.M117.817635
doi: 10.1074/jbc.M117.817635
pubmed: 29343514
pmcid: 5846146
Thomas LW, Ashcroft M (2019) Exploring the molecular interface between hypoxia-inducible factor signalling and mitochondria. Cell Mol Life Sci 76:1759–1777. https://doi.org/10.1007/s00018-019-03039-y
doi: 10.1007/s00018-019-03039-y
pubmed: 30767037
pmcid: 6453877
Patel SA, Simon MC (2008) Biology of hypoxia-inducible factor-2alpha in development and disease. Cell Death Differ 15:628–634. https://doi.org/10.1038/cdd.2008.17
doi: 10.1038/cdd.2008.17
pubmed: 18259197
Flynn JM, Melov S (2013) SOD2 in mitochondrial dysfunction and neurodegeneration. Free Radic Biol Med 62:4–12. https://doi.org/10.1016/j.freeradbiomed.2013.05.027
doi: 10.1016/j.freeradbiomed.2013.05.027
Shneor D, Folberg R, Pe’er J, et al (2017) Stable knockdown of CREB, HIF-1 and HIF-2 by replication-competent retroviruses abrogates the responses to hypoxia in hepatocellular carcinoma. Cancer Gene Ther 24:64–74. https://doi.org/10.1038/cgt.2016.68
doi: 10.1038/cgt.2016.68
pubmed: 27934882
Bertout JA, Majmundar AJ, Gordan JD et al (2009) HIF2α inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proc Natl Acad Sci 106:14391–14396. https://doi.org/10.1073/pnas.0907357106
doi: 10.1073/pnas.0907357106
pubmed: 19706526
pmcid: 2726037
Li NA, Wang H, Zhang J, Zhao E (2016) Knockdown of hypoxia inducible factor-2α inhibits cell invasion via the downregulation of MMP-2 expression in breast cancer cells. Oncol Lett 11:3743–3748. https://doi.org/10.3892/ol.2016.4471
doi: 10.3892/ol.2016.4471
pubmed: 27313686
pmcid: 4888230
Brown ST, Nurse CA (2008) Induction of HIF-2alpha is dependent on mitochondrial O2 consumption in an O2-sensitive adrenomedullary chromaffin cell line. Am J Physiol Cell Physiol 294:C1305–C1312. https://doi.org/10.1152/ajpcell.00007.2008
doi: 10.1152/ajpcell.00007.2008
pubmed: 18353899
Keith B, Johnson RS, Simon MC (2011) HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12:9–22. https://doi.org/10.1038/nrc3183
doi: 10.1038/nrc3183
pubmed: 22169972
pmcid: 3401912
Imamura T, Kikuchi H, Herraiz M-T et al (2009) HIF-1alpha and HIF-2alpha have divergent roles in colon cancer. Int J cancer 124:763–771. https://doi.org/10.1002/ijc.24032
doi: 10.1002/ijc.24032
pubmed: 19030186
pmcid: 2682346
Zhu C, Yu J, Pan Q et al (2016) Hypoxia-inducible factor-2 alpha promotes the proliferation of human placenta-derived mesenchymal stem cells through the MAPK/ERK signaling pathway. Sci Rep 6:35489. https://doi.org/10.1038/srep35489
doi: 10.1038/srep35489
pubmed: 27765951
pmcid: 5073233
Thompson AAR, Elks PM, Marriott HM et al (2014) Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish. Blood 123:366–376. https://doi.org/10.1182/blood-2013-05-500207
doi: 10.1182/blood-2013-05-500207
pubmed: 24196071
pmcid: 3894493
Davis L, Recktenwald M, Hutt E et al (2022) Targeting HIF-2α in the tumor microenvironment: redefining the role of HIF-2α for solid cancer therapy. Cancers (Basel). https://doi.org/10.3390/cancers14051259
doi: 10.3390/cancers14051259
pubmed: 36291932
pmcid: 8988100
Su R, Ma J, Zheng J et al (2020) PABPC1-induced stabilization of BDNF-AS inhibits malignant progression of glioblastoma cells through STAU1-mediated decay. Cell Death Dis 11:81. https://doi.org/10.1038/s41419-020-2267-9
doi: 10.1038/s41419-020-2267-9
pubmed: 32015336
pmcid: 6997171
Jing F, Ruan X, Liu X et al (2020) The PABPC5/HCG15/ZNF331 feedback loop regulates vasculogenic mimicry of glioma via STAU1-mediated mRNA decay. Mol Ther oncolytics 17:216–231. https://doi.org/10.1016/j.omto.2020.03.017
doi: 10.1016/j.omto.2020.03.017
pubmed: 32346611
pmcid: 7183103