Roles of regulator of chromosome condensation 2 in cancer: Beyond its regulatory function in cell cycle

Abstract

Regulator of chromosome condensation 2 (RCC2) is an essential protein in order for mitosis to proceed properly. It localizes in the centrosome of chromosomes where is involved in chromosome segregation and cytokinesis. Furthermore, RCC2 associates with integrin networks at the plasma membrane where participates in the control of cell movement. Because of its known role in cell cycle, RCC2 has been linked with cancer progression. Several reports show that RCC2 induces cancer hallmarks, but the mechanisms explaining how RCC2 exerts these roles are widely unknown. Here, we aim to summarize the main findings explaining the roles and mechanisms of RCC2 in cancer promotion. RCC2 is overexpressed in different cancers, including glioblastoma, lung, ovarian, and esophageal which is related to proliferation, migration, invasion promotion in vitro and tumor progression and metastasis in vivo. Besides, RCC2 overexpression induces epithelial-mesenchymal transition and causes poorer prognosis in cancer patients. RCC2 overexpression has also been linked with resistance development to chemotherapy and radiotherapy by inhibiting apoptosis and activating cancer-promoting transcription factors. Unfortunately, not RCC2 inhibitors are currently available for further pre-clinical and clinical assays. Therefore, these findings emphasize the potential use of RCC2 as a targetable biomarker in cancer and highlight the importance for designing RCC2 chemical inhibitors to evaluate its efficacy in animal studies and clinical trials.

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References

Andreassen PR, Palmer DK, Wener MH, Margolis RL. Telophase disc: a new mammalian mitotic organelle that bisects telophase cells with a possible function in cytokinesis. J Cell Sci 1991;99:523-34.

Mollinari C, Reynaud C, Martineau-Thuillier S, et al. The mammalian passenger protein TD-60 is an RCC1 family member with an essential role in prometaphase to metaphase progression. Dev Cell 2003;5:295-307. DOI: https://doi.org/10.1016/S1534-5807(03)00205-3

Carmena M, Wheelock M, Funabiki H, Earnshaw WC. The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis. Nat Rev Mol Cell Biol 2012;13:789-803. DOI: https://doi.org/10.1038/nrm3474

Adams RR, Carmena M, Earnshaw WC. Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol 2001;11:49-54. DOI: https://doi.org/10.1016/S0962-8924(00)01880-8

Vader G, Medema RH, Lens SMA. The chromosomal passenger complex: guiding Aurora-B through mitosis. J Cell Biol 2006;173:833-37. DOI: https://doi.org/10.1083/jcb.200604032

Martineau-Thuillier S, Andreassen PR, Margolis RL. Colocalization of TD-60 and INCENP throughout G2 and mitosis: evidence for their possible interaction in signalling cytokinesis. Chromosoma 1998;107:461-70. DOI: https://doi.org/10.1007/s004120050330

Gassmann R, Carvalho A, Henzing AJ, et al. Borealin: a novel chromosomal passenger required for stability of the bipolar mitotic spindle. J Cell Biol 2004;166:179-91. DOI: https://doi.org/10.1083/jcb.200404001

Grigera PR, Ma L, Borgman CA, et al. Mass spectrometric analysis identifies a cortactin-RCC2/TD60 interaction in mitotic cells. J Proteomics 2012;75:2153-9. DOI: https://doi.org/10.1016/j.jprot.2012.01.012

Papini D, Langemeyer L, Abad MA, et al. TD-60 links RalA GTPase function to the CPC in mitosis. Nat Commun 2015;6:7678. DOI: https://doi.org/10.1038/ncomms8678

Wu N, Ren D, Li S, et al. RCC2 over-expression in tumor cells alters apoptosis and drug sensitivity by regulating Rac1 activation. BMC Cancer 2018;18:67. DOI: https://doi.org/10.1186/s12885-017-3908-y

Williamson RC, Cowell CA, Hammond CL, et al. Coronin-1C and RCC2 guide mesenchymal migration by trafficking Rac1 and controlling GEF exposure. J Cell Sci 2014;127:4292-307. DOI: https://doi.org/10.1242/jcs.154864

Rosasco-Nitcher SE, Lan W, Khorasanizadeh S, Stukenberg PT. Centromeric Aurora-B activation requires TD-60, microtubules, and substrate priming phosphorylation. Science 2008;319:469-72. DOI: https://doi.org/10.1126/science.1148980

Yenjerla M, Panopoulos A, Reynaud C, et al. TD-60 is required for interphase cell cycle progression. Cell Cycle 2013;12:837-41. DOI: https://doi.org/10.4161/cc.23821

Carmona-Fontaine C, Matthews H, Mayor R. Directional cell migration in vivo: Wnt at the crest. Cell Adhes Migr 2008;2:240-42. DOI: https://doi.org/10.4161/cam.2.4.6747

Friedl P, Gilmour D. Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 2009;10:445-57. DOI: https://doi.org/10.1038/nrm2720

Alblazi KM, Siar CH. Cellular protrusions--lamellipodia, filopodia, invadopodia and podosomes--and their roles in progression of orofacial tumours: current understanding. Asian Pac J Cancer P 2015;16:2187-91. DOI: https://doi.org/10.7314/APJCP.2015.16.6.2187

Pollard TD, Borisy GG. Cellular motility driven by assembly and disassembly of actin filaments. Cell 2003;112:453-65. DOI: https://doi.org/10.1016/S0092-8674(03)00120-X

Humphries JD, Byron A, Bass MD, et al. Proteomic analysis of integrin-associated complexes identifies RCC2 as a dual regulator of Rac1 and Arf6. Sci Signal 2009;2:ra51. DOI: https://doi.org/10.1126/scisignal.2000396

Atkinson SJ, Gontarczyk AM, Alghamdi AA, et al. The β3-integrin endothelial adhesome regulates microtubule-dependent cell migration. EMBO Rep 2018;19:e44578. DOI: https://doi.org/10.15252/embr.201744578

Jeanes AI, Wang P, Moreno-Layseca P, et al. Specific β-containing integrins exert differential control on proliferation and two-dimensional collective cell migration in mammary epithelial cells. J Biol Chem 2012;287:24103-12. DOI: https://doi.org/10.1074/jbc.M112.360834

Matsuo M, Nakada C, Tsukamoto Y, et al. MiR-29c is downregulated in gastric carcinomas and regulates cell proliferation by targeting RCC2. Mol Cancer 2013;12:15. DOI: https://doi.org/10.1186/1476-4598-12-15

Rendleman J, Shang S, Dominianni C, et al. Melanoma risk loci as determinants of melanoma recurrence and survival. J Transl Med 2013;11:279. DOI: https://doi.org/10.1186/1479-5876-11-279

Fujii K, Miyata Y, Takahashi I, et al. Differential proteomic analysis between small cell lung carcinoma (SCLC) and pulmonary carcinoid tumors reveals molecular signatures for malignancy in lung cancer. Proteomics Clin Appl 2018;12:e1800015. DOI: https://doi.org/10.1002/prca.201800015

Pang B, Wu N, Guan R, et al. Overexpression of RCC2 enhances cell motility and promotes tumor metastasis in lung adenocarcinoma by inducing epithelial-mesenchymal transition. Clin Cancer Res 2017;23:5598-610. DOI: https://doi.org/10.1158/1078-0432.CCR-16-2909

Yu H, Zhang S, Ibrahim AN, et al. RCC2 promotes proliferation and radio-resistance in glioblastoma via activating transcription of DNMT1. Biochem Biophysical Res Co 2019;516:999-1006. DOI: https://doi.org/10.1016/j.bbrc.2019.06.097

Chen Z, Wu W, Huang Y, et al. RCC2 promotes breast cancer progression through regulation of Wnt signaling and inducing EMT. J Cancer 2019;10:6837-47. DOI: https://doi.org/10.7150/jca.36430

Bruun J, Kolberg M, Ahlquist TC, et al. Regulator of chromosome condensation 2 identifies high-risk patients within both major phenotypes of colorectal cancer. Clin Cancer Res 2015;21:3759-70. DOI: https://doi.org/10.1158/1078-0432.CCR-14-3294

Gong S, Chen Y, Meng F, et al. RCC2, a regulator of the RalA signaling pathway is identified as a novel therapeutic target in cisplatin-resistant ovarian cancer. FASEB J 2019;33:5350-65. DOI: https://doi.org/10.1096/fj.201801529RR

Calderon-Aparicio A, Yamamoto H, De Vitto H, et al. RCC2 promotes esophageal cancer growth by regulating activity and expression of the Sox2 transcription factor. Mol Cancer Res 2020 [Epub ahead of print]. DOI: https://doi.org/10.1158/1538-7445.AM2020-2469

Chanukuppa V, Paul D, Taunk K, et al. XPO1 is a critical player for bortezomib resistance in multiple myeloma: A quantitative proteomic approach. J Proteomics 2019;209:103504. DOI: https://doi.org/10.1016/j.jprot.2019.103504

Buranjiang G, Kuerban R, Abuduwanke A, et al. MicroRNA-331-3p inhibits proliferation and metastasis of ovarian cancer by targeting RCC2. Arch Med Sci 2019;15:1520-9. DOI: https://doi.org/10.5114/aoms.2018.77858

Lin H, Zhang X, Feng N, et al. LncRNA LCPAT1 mediates smoking/particulate matter 2.5-induced cell autophagy and epithelial-mesenchymal transition in lung cancer cells via RCC2. Cell Physiol Biochem 2018;47:1244-58. DOI: https://doi.org/10.1159/000490220

Song C, Liang L, Jin Y, et al. RCC2 is a novel p53 target in suppressing metastasis. Oncogene 2018;37:8-17. DOI: https://doi.org/10.1038/onc.2017.306

Engels BM, Hutvagner G. Principles and effects of microRNA-mediated post-transcriptional gene regulation. Oncogene 2006;25:6163-9. DOI: https://doi.org/10.1038/sj.onc.1209909

Yi JM, Kang EJ, Kwon HM, et al. Epigenetically altered miR-1247 functions as a tumor suppressor in pancreatic cancer. Oncotarget 2017;8:26600-12. DOI: https://doi.org/10.18632/oncotarget.15722

Published
2021-03-19
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Section
Reviews
Keywords:
RCC2, cancer progression, metastasis, oncogene.
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How to Cite
Calderon-Aparicio, A., & Bode, A. (2021). Roles of regulator of chromosome condensation 2 in cancer: Beyond its regulatory function in cell cycle. Oncology Reviews, 15(1). https://doi.org/10.4081/oncol.2021.525