Abstract
CDGSH iron sulfur domain 2 (CISD2) is reported to be highly expressed in several cancers, but the role of it in neuroblastoma has not been identified yet. Here, for the first time, we show that CISD2 is involved in neuroblastoma tumorigenesis and regulates neuroblastoma cell proliferation and differentiation. We found that high CISD2 expression correlated significantly with poor outcome of neuroblastoma patients, as well as advanced neuroblastoma tumor stages. Knockdown of CISD2 greatly repressed neuroblastoma cell proliferation and tumorigenesis both in vitro and in vivo. Further investigation showed that CISD2 deficiency resulted in cell cycle arrest in G1 phase and induced cell differentiation of neuroblastoma. Several Cyclins and Cyclin-Dependent Kinases (CDKs) were down-regulated by CISD2 knockdown, indicating that CISD2 probably regulates cell cycle through those genes. Together, we provide evidence that CISD2 is an indicator for neuroblastoma patients prognosis and is indispensable for neuroblastoma cell proliferation and tumorigenesis; CISD2 deficiency can induce neuroblastoma cell cycle arrest and differentiation. These findings suggest that CISD2 could work as a novel and potential therapeutic target for neuroblastoma treatment.
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Abbreviations
- BrdU:
-
5-Bromo-2-deoxyuridine
- CDK:
-
Cyclin-Dependent Kinase
- CISD2:
-
CDGSH iron sulfur domain 2
- DMEM:
-
Dulbecco’s modified Eagle’s medium
- FBS:
-
fetal bovine serum
- shRNA:
-
short hairpin RNA
References
Brodeur GM (2003) Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3(3):203–216
Takeuchi LA, Hachitanda Y, Woods WG, Tuchman M, Lemieux B, Brisson L, Bernstein M, Brossard J, Leclerc JM, Byrne TD et al (1995) Screening for neuroblastoma in North America. Preliminary results of a pathology review from the Quebec project. Cancer 76(11):2363–2371
Anderson DJ (1997) Cellular and molecular biology of neural crest cell lineage determination. Trend Genet: TIG 13(7):276–280
Nishi M, Miyake H, Takeda T, Yonemori H, Hanai J, Kikuchi Y, Takasugi N (1994) A trial to discriminate spontaneous regression from non-regression cases during mass screening for neuroblastoma. Jpn J Clin Oncol 24(5):247–251
Negroni A, Scarpa S, Romeo A, Ferrari S, Modesti A, Raschella G (1991) Decrease of proliferation rate and induction of differentiation by a Mycn antisense DNA oligomer in a human Neuroblastoma cell-line. Cell Growth Differ 2(10):511–518
Manohar CF, Salwen HR, Furtado MR, Cohn SL (1996) Up-regulation of HOXC6, HOXD1, and HOXD8 homeobox gene expression in human neuroblastoma cells following chemical induction of differentiation. Tumour Biol 17(1):34–47
Zhang X, Hamada J, Nishimoto A, Takahashi Y, Murai T, Tada M, Moriuchi T (2007) HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells. J Cell Mol Med 11(2):299–306
Conlan AR, Axelrod HL, Cohen AE, Abresch EC, Zuris J, Yee D, Nechushtai R, Jennings PA, Paddock ML (2009) Crystal structure of Miner1: the redox-active 2Fe-2S protein causative in Wolfram syndrome 2. J Mol Biol 392(1):143–153
Paddock ML, Wiley SE, Axelrod HL, Cohen AE, Roy M, Abresch EC, Capraro D, Murphy AN, Nechushtai R, Dixon JE, Jennings PA (2007) MitoNEET is a uniquely folded 2Fe 2S outer mitochondrial membrane protein stabilized by pioglitazone. Proc Natl Acad Sci U S A 104(36):14342–14347
Chen YF, Kao CH, Kirby R, Tsai TF (2009) Cisd2 mediates mitochondrial integrity and life span in mammals. Autophagy 5(7):1043–1045
Wu CY, Chen YF, Wang CH, Kao CH, Zhuang HW, Chen CC, Chen LK, Kirby R, Wei YH, Tsai SF, Tsai TF (2012) A persistent level of Cisd2 extends healthy lifespan and delays aging in mice. Hum Mol Genet 21(18):3956–3968
Liu L, Xia M, Wang J, Zhang W, Zhang Y, He M (2014) CISD2 expression is a novel marker correlating with pelvic lymph node metastasis and prognosis in patients with early-stage cervical cancer. Med Oncol 31(9):183
Chen B, Shen S, Wu J, Hua Y, Kuang M, Li S, Peng B (2015) CISD2 associated with proliferation indicates negative prognosis in patients with hepatocellular carcinoma. Int J Clin Exp Pathol 8(10):13725–13738
Yang L, Hong S, Wang Y, He Z, Liang S, Chen H, He S, Wu S, Song L, Chen Y (2016) A novel prognostic score model incorporating CDGSH iron sulfur domain2 (CISD2) predicts risk of disease progression in laryngeal squamous cell carcinoma. Oncotarget 7(16):22720–22732
Sohn YS, Tamir S, Song L, Michaeli D, Matouk I, Conlan AR, Harir Y, Holt SH, Shulaev V, Paddock ML, Hochberg A, Cabanchick IZ, Onuchic JN, Jennings PA, Nechushtai R, Mittler R (2013) NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth. Proc Natl Acad Sci U S A 110(36):14676–14681
Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, De Bernardi B, Evans AE, Favrot M, Hedborg F et al (1994) Revisions of the international criteria for neuroblastoma diagnosis, staging and response to treatment. Prog Clin Biol Res 385:363–369
Schmidt ML, Lal A, Seeger RC, Maris JM, Shimada H, O'Leary M, Gerbing RB, Matthay KK (2005) Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer group study. J Clin Oncol 23(27):6474–6480
Fredlund E, Ringner M, Maris JM, Pahlman S (2008) High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Proc Natl Acad Sci U S A 105(37):14094–14099
Mao L, Ding J, Zha YH, Yang LQ, McCarthy BA, King W, Cui HJ, Ding HF (2011) HOXC9 links cell-cycle exit and neuronal differentiation and is a prognostic marker in Neuroblastoma. Cancer Res 71(12):4314–4324
Sihag RK, Jaffe H, Nixon RA, Rong XH (1999) Serine-23 is a major protein kinase a phosphorylation site on the amino-terminal head domain of the middle molecular mass subunit of neurofilament proteins. J Neurochem 72(2):491–499
Chang L, Goldman RD (2004) Intermediate filaments mediate cytoskeletal crosstalk. Nature reviews. Mol Cell Biol 5(8):601–613
Eriksson KS, Zhang SW, Lin L, Lariviere RC, Julien JP, Mignot E (2008) The type III neurofilament peripherin is expressed in the tuberomammillary neurons of the mouse. BMC Neurosci 9
Kageyama R, Ishibashi M, Takebayashi K, Tomita K (1997) bHLH transcription factors and mammalian neuronal differentiation. Int J Biochem Cell Biol 29(12):1389–1399
Tamir S, Zuris JA, Agranat L, Lipper CH, Conlan AR, Michaeli D, Harir Y, Paddock ML, Mittler R, Cabantchik ZI, Jennings PA, Nechushtai R (2013) Nutrient-deprivation autophagy factor-1 (NAF-1): biochemical properties of a novel cellular target for anti-diabetic drugs. PLoS One 8(5):e61202
Huang MY, Xuan F, Liu W, Cui HJ (2017) MINA controls proliferation and tumorigenesis of glioblastoma by epigenetically regulating cyclins and CDKs via H3K9me3 demethylation. Oncogene 36(3):387–396
Murray AW (1992) Creative blocks - cell-cycle checkpoints and feedback controls. Nature 359(6396):599–604
Evans AE, D'Angio GJ, Randolph J (1971) A proposed staging for children with neuroblastoma. Children's cancer study group a. Cancer 27(2):374–378
Haas D, Ablin AR, Miller C, Zoger S, Matthay KK (1988) Complete pathologic maturation and regression of stage IVS neuroblastoma without treatment. Cancer 62(4):818–825
Westermark UK, Wilhelm M, Frenzel A, Henriksson MA (2011) The MYCN oncogene and differentiation in neuroblastoma. Semin Cancer Biol 21(4):256–266
Xuan F, Huang M, Liu W, Ding H, Yang L, Cui H (2016) Homeobox C9 suppresses Beclin1-mediated autophagy in glioblastoma by directly inhibiting the transcription of death-associated protein kinase 1. Neuro-Oncology 18(6):819–829
Yang L, Huang M, Tan J, Hou J, He J, Wang F, Cui H, Yi L (2017) Transcriptional co-activator with PDZ-binding motif overexpression promotes cell proliferation and transcriptional co-activator with PDZ-binding motif deficiency induces cell cycle arrest in neuroblastoma. Oncol Lett 13(6):4295–4301
Xuan F, Huang M, Zhao E, Cui H (2018) MINA53 deficiency leads to glioblastoma cell apoptosis via inducing DNA replication stress and diminishing DNA damage response. Cell Death Dis 9(11):1062
Acknowledgments
This work was supported by the National Key Research and Development Program of China (2017YFC1308600, 2016YFC1302204), the National Natural Science Foundation of China (No. 81672502), the Entrepreneurship and Innovation Program for Chongqing Overseas Returned Scholars (No. cx2017014), and the Chongqing University Innovation Team Building Program funded projects (CXTDX201601010).
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The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.
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Li, J., Duan, H., Xuan, F. et al. CDGSH Iron Sulfur Domain 2 Deficiency Inhibits Cell Proliferation and Induces Cell Differentiation of Neuroblastoma. Pathol. Oncol. Res. 26, 1725–1733 (2020). https://doi.org/10.1007/s12253-019-00753-7
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DOI: https://doi.org/10.1007/s12253-019-00753-7