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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

BUB1B Promotes Proliferation of Prostate Cancer via Transcriptional Regulation of MELK

Author(s): Juan-Hua Tian, Li-Jun Mu, Mei-Yu Wang, Jin Zeng, Qing-Zhi Long, Bin Guan, Wen Wang, Yu-Mei Jiang, Xiao-Jing Bai and Yue-Feng Du*

Volume 20, Issue 9, 2020

Page: [1140 - 1146] Pages: 7

DOI: 10.2174/1871520620666200101141934

Price: $65

Abstract

Background: Prostate cancer remains one of the most common and deadliest forms of cancer, generally respond well to radical prostatectomy and associated interventions, up to 30% of individuals will suffer disease relapse. Although BUB1B was found to be essential for cell growth and proliferation, even in several kinds of tumor cells, the specific importance and mechanistic role of BUB1B in prostate cancer remain unclear.

Methods: Quantitative Real-Time PCR and Western-blot were used in the detection of mRNA and protein expression. Lentivirus infection was used to overexpression or knock down the target gene. Flow cytometry analysis was performed to test protein expression and apoptosis level. Immunohistochemistry was used to identify protein expression in tissue. Statistical differences between the two groups are evaluated by two-tailed t-tests. The comparison among multiple groups is performed by one-way Analysis of Variance (ANOVA) followed by Dunnett’s posttest. The statistical significance of the Kaplan-Meier survival plot is determined by log-rank analysis.

Results: In the present report, we found BUB1B expression to be highly increased in prostate cancer tissues relative to normal controls. We further found BUB1B to be essential for efficient tumor cell proliferation, and to correlate with poorer prostate cancer patient outcomes. From a mechanistic perspective, the ability of BUB1B to regulate MELK was found to be essential for its ability to promote prostate cancer cell proliferation.

Conclusion: Altogether, our data suggest that BUB1B is up-regulated in prostate cancer, suggesting that the growth of cancer cells may depend on BUB1B-dependent regulation of MELK transcription. BUB1B may serve as a clinical prognostic factor and a druggable target for prostate cancer.

Keywords: BUB1B, prostate cancer, MELK, transcriptional regulation, PCR, western-blot.

Graphical Abstract
[1]
Narayan, V.M.; Konety, B.R.; Warlick, C. Novel biomarkers for prostate cancer: An evidence-based review for use in clinical practice. Int. J. Urol., 2017, 24(5), 352-360.
[2]
Jakobsen, N.A.; Hamdy, F.C.; Bryant, R.J. Novel biomarkers for the detection of prostate cancer. J. Clin. Urol., 2016, 9(2)(Suppl.), 3-10.
[http://dx.doi.org/10.1177/2051415816656121] [PMID: 28344810]
[3]
Qian, B.; Yao, Y.; Liu, C.; Zhang, J.; Chen, H.; Li, H. SU6668 modulates prostate cancer progression by downregulating MTDH/AKT signaling pathway. Int. J. Oncol., 2017, 50(5), 1601-1611.
[http://dx.doi.org/10.3892/ijo.2017.3926] [PMID: 28339027]
[4]
Antonarakis, E.S.; Feng, Z.; Trock, B.J.; Humphreys, E.B.; Carducci, M.A.; Partin, A.W.; Walsh, P.C.; Eisenberger, M.A. The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: Long-term follow-up. BJU Int., 2012, 109(1), 32-39.
[http://dx.doi.org/10.1111/j.1464-410X.2011.10422.x] [PMID: 21777360]
[5]
Annala, M.; Struss, W.J.; Warner, E.W.; Beja, K.; Vandekerkhove, G.; Wong, A.; Khalaf, D.; Seppälä, I.L.; So, A.; Lo, G.; Aggarwal, R.; Small, E.J.; Nykter, M.; Gleave, M.E.; Chi, K.N.; Wyatt, A.W. Treatment outcomes and tumor loss of heterozygosity in germline DNA repair-deficient prostate cancer. Eur. Urol., 2017, 72(1), 34-42.
[http://dx.doi.org/10.1016/j.eururo.2017.02.023] [PMID: 28259476]
[6]
Sakai, Y.; Komai, Y.; Saito, N.; Ito, M.; Sakuraba, M. Analysis of a surgical treatment for persistent urorectal fistulas after radical cancer surgery: A comparison of prostate cancer and rectal cancer. Urol. Int., 2017, 99(1), 56-62.
[http://dx.doi.org/10.1159/000457835] [PMID: 28231570]
[7]
Wang, L.; Wang, B.; Ai, Q.; Zhang, Y.; Lv, X.; Li, H.; Ma, X.; Zhang, X. Long-term cancer control outcomes of robot-assisted radical prostatectomy for prostate cancer treatment: A meta-analysis. Int. Urol. Nephrol., 2017, 49(6), 995-1005.
[http://dx.doi.org/10.1007/s11255-017-1552-8] [PMID: 28238148]
[8]
Bakht, M.K.; Oh, S.W.; Hwang, D.W.; Lee, Y.S.; Youn, H.; Porter, L.A.; Cheon, G.J.; Kwak, C.; Lee, D.S.; Kang, K.W. The potential roles of radionanomedicine and radioexosomic in prostate cancer research and treatment. Curr. Pharm. Des., 2017, 23(20), 2976-2990.
[http://dx.doi.org/10.2174/1381612823666170216122412] [PMID: 28215159]
[9]
Taylor, S.S.; Ha, E.; McKeon, F. The human homologue of BUB3 is required for kinetochore localization of BUB1 and a Mad3/BUB1-related protein kinase. J. Cell Biol., 1998, 142(1), 1-11.
[http://dx.doi.org/10.1083/jcb.142.1.1] [PMID: 9660858]
[10]
Baker, D.J.; Jeganathan, K.B.; Cameron, J.D.; Thompson, M.; Juneja, S.; Kopecka, A.; Kumar, R.; Jenkins, R.B.; de Groen, P.C.; Roche, P.; van Deursen, J.M. BUBR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat. Genet., 2004, 36(7), 744-749.
[http://dx.doi.org/10.1038/ng1382] [PMID: 15208629]
[11]
Dai, W.; Wang, Q.; Liu, T.; Swamy, M.; Fang, Y.; Xie, S.; Mahmood, R.; Yang, Y.M.; Xu, M.; Rao, C.V. Slippage of mitotic arrest and enhanced tumor development in mice with BUBR1 haploinsufficiency. Cancer Res., 2004, 64(2), 440-445.
[http://dx.doi.org/10.1158/0008-5472.CAN-03-3119] [PMID: 14744753]
[12]
Wang, Q.; Liu, T.; Fang, Y.; Xie, S.; Huang, X.; Mahmood, R.; Ramaswamy, G.; Sakamoto, K.M.; Darzynkiewicz, Z.; Xu, M.; Dai, W. BUBR1 deficiency results in abnormal megakaryopoiesis. Blood, 2004, 103(4), 1278-1285.
[http://dx.doi.org/10.1182/blood-2003-06-2158] [PMID: 14576056]
[13]
Kops, G.J.; Foltz, D.R.; Cleveland, D.W. Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. Proc. Natl. Acad. Sci. USA, 2004, 101(23), 8699-8704.
[http://dx.doi.org/10.1073/pnas.0401142101] [PMID: 15159543]
[14]
Wan, X.; Yeung, C.; Kim, S.Y.; Dolan, J.G.; Ngo, V.N.; Burkett, S.; Khan, J.; Staudt, L.M.; Helman, L.J. Identification of FoxM1/Bub1b signaling pathway as a required component for growth and survival of rhabdomyosarcoma. Cancer Res., 2012, 72(22), 5889-5899.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-1991] [PMID: 23002205]
[15]
Hudler, P.; Britovsek, N.K.; Grazio, S.F.; Komel, R. Association between polymorphisms in segregation genes BUB1B and TTK and gastric cancer risk. Radiol. Oncol., 2016, 50(3), 297-307.
[http://dx.doi.org/10.1515/raon-2015-0047] [PMID: 27679546]
[16]
Mansouri, N.; Movafagh, A.; Sayad, A.; Heidary Pour, A.; Taheri, M.; Soleimani, S.; Mirzaei, H.R.; Alizadeh Shargh, S.; Azargashb, E.; Bazmi, H.; Allah Moradi, H.; Zandnia, F.; Hashemi, M.; Massoudi, N.; Mortazavi-Tabatabaei, S.A. Targeting of BUB1b gene expression in sentinel lymph node biopsies of invasive breast cancer in Iranian female patients. Asian Pac. J. Cancer Prev., 2016, 17(S3), 317-321.
[http://dx.doi.org/10.7314/APJCP.2016.17.S3.317] [PMID: 27165245]
[17]
Hahn, M.M.; Vreede, L.; Bemelmans, S.A.; van der Looij, E.; van Kessel, A.G.; Schackert, H.K.; Ligtenberg, M.J.; Hoogerbrugge, N.; Kuiper, R.P.; de Voer, R.M. Prevalence of germline mutations in the spindle assembly checkpoint gene BUB1B in individuals with early-onset colorectal cancer. Genes Chromosomes Cancer, 2016, 55(11), 855-863.
[http://dx.doi.org/10.1002/gcc.22385] [PMID: 27239782]
[18]
Minata, M.; Gu, C.; Joshi, K.; Nakano-Okuno, M.; Hong, C.; Nguyen, C.H.; Kornblum, H.I.; Molla, A.; Nakano, I. Multi-kinase inhibitor C1 triggers mitotic catastrophe of glioma stem cells mainly through MELK kinase inhibition. PLoS One, 2014, 9(4)e92546
[http://dx.doi.org/10.1371/journal.pone.0092546] [PMID: 24739874]
[19]
Simon, M.; Mesmar, F.; Helguero, L.; Williams, C. Genome-wide effects of MELK-inhibitor in triple-negative breast cancer cells indicate context-dependent response with p53 as a key determinant. PLoS One, 2017, 12(2)e0172832
[http://dx.doi.org/10.1371/journal.pone.0172832] [PMID: 28235006]
[20]
Kuner, R.; Fälth, M.; Pressinotti, N.C.; Brase, J.C.; Puig, S.B.; Metzger, J.; Gade, S.; Schäfer, G.; Bartsch, G.; Steiner, E.; Klocker, H.; Sültmann, H. The Maternal Embryonic Leucine zipper Kinase (MELK) is upregulated in high-grade prostate cancer. J. Mol. Med. (Berl.), 2013, 91(2), 237-248.
[http://dx.doi.org/10.1007/s00109-012-0949-1] [PMID: 22945237]
[21]
Kohler, R.S.; Kettelhack, H.; Knipprath-Mészaros, A.M.; Fedier, A.; Schoetzau, A.; Jacob, F.; Heinzelmann-Schwarz, V. MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells. Gynecol. Oncol., 2017, 145(1), 159-166.
[http://dx.doi.org/10.1016/j.ygyno.2017.02.016] [PMID: 28214016]
[22]
Inoue, H.; Kato, T.; Olugbile, S.; Tamura, K.; Chung, S.; Miyamoto, T.; Matsuo, Y.; Salgia, R.; Nakamura, Y.; Park, J.H. Effective growth-suppressive activity of Maternal Embryonic Leucine-zipper Kinase (MELK) inhibitor against small cell lung cancer. Oncotarget, 2016, 7(12), 13621-13633.
[http://dx.doi.org/10.18632/oncotarget.7297] [PMID: 26871945]
[23]
Nakano, I.; Paucar, A.A.; Bajpai, R.; Dougherty, J.D.; Zewail, A.; Kelly, T.K.; Kim, K.J.; Ou, J.; Groszer, M.; Imura, T.; Freije, W.A.; Nelson, S.F.; Sofroniew, M.V.; Wu, H.; Liu, X.; Terskikh, A.V.; Geschwind, D.H.; Kornblum, H.I. Maternal Embryonic Leucine zipper Kinase (MELK) regulates multipotent neural progenitor proliferation. J. Cell Biol., 2005, 170(3), 413-427.
[http://dx.doi.org/10.1083/jcb.200412115] [PMID: 16061694]
[24]
Rajkumar, T.; Sabitha, K.; Vijayalakshmi, N.; Shirley, S.; Bose, M.V.; Gopal, G.; Selvaluxmy, G. Identification and validation of genes involved in cervical tumourigenesis. BMC Cancer, 2011, 11, 80.
[http://dx.doi.org/10.1186/1471-2407-11-80] [PMID: 21338529]
[25]
Beke, L.; Kig, C.; Linders, J.T.; Boens, S.; Boeckx, A.; van Heerde, E.; Parade, M.; De Bondt, A.; Van den Wyngaert, I.; Bashir, T.; Ogata, S.; Meerpoel, L.; Van Eynde, A.; Johnson, C.N.; Beullens, M.; Brehmer, D.; Bollen, M. MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells. Biosci. Rep., 2015, 35(6)e00267
[http://dx.doi.org/10.1042/BSR20150194] [PMID: 26431963]
[26]
Karess, R.E.; Wassmann, K.; Rahmani, Z. New insights into the role of BubR1 in mitosis and beyond. Int. Rev. Cell Mol. Biol., 2013, 306, 223-273.
[http://dx.doi.org/10.1016/B978-0-12-407694-5.00006-7] [PMID: 24016527]
[27]
Hoffman, D.B.; Pearson, C.G.; Yen, T.J.; Howell, B.J.; Salmon, E.D. Microtubule-dependent changes in assembly of microtubule motor proteins and mitotic spindle checkpoint proteins at PtK1 kinetochores. Mol. Biol. Cell, 2001, 12(7), 1995-2009.
[http://dx.doi.org/10.1091/mbc.12.7.1995] [PMID: 11451998]
[28]
Guo, X.; Liu, A.; Hua, H.; Lu, H.; Zhang, D.; Lin, Y.; Sun, Q.; Zhu, X.; Yan, G.; Zhao, F.; Siomycin, A. Siomycin A induces apoptosis in human lung adenocarcinoma A549 cells by suppressing the expression of FOXM1. Nat. Prod. Commun., 2015, 10(9), 1603-1606.
[http://dx.doi.org/10.1177/1934578X1501000929] [PMID: 26594769]
[29]
Nakano, I.; Joshi, K.; Visnyei, K.; Hu, B.; Watanabe, M.; Lam, D.; Wexler, E.; Saigusa, K.; Nakamura, Y.; Laks, D.R.; Mischel, P.S.; Viapiano, M.; Kornblum, H.I. Siomycin A targets brain tumor stem cells partially through a MELK-mediated pathway. Neuro-oncol., 2011, 13(6), 622-634.
[http://dx.doi.org/10.1093/neuonc/nor023] [PMID: 21558073]
[30]
Bhat, U.G.; Halasi, M.; Gartel, A.L. Thiazole antibiotics target FoxM1 and induce apoptosis in human cancer cells. PLoS One, 2009, 4(5)e5592
[http://dx.doi.org/10.1371/journal.pone.0005592] [PMID: 19440351]
[31]
Adami, G.R.; Ye, H. Future roles for FOXM1 inhibitors in cancer treatments. Future Oncol., 2007, 3(1), 1-3.
[http://dx.doi.org/10.2217/14796694.3.1.1] [PMID: 17280494]
[32]
Bolanos-Garcia, V.M.; Blundell, T.L. BUB1 and BUBR1: Multifaceted kinases of the cell cycle. Trends Biochem. Sci., 2011, 36(3), 141-150.
[http://dx.doi.org/10.1016/j.tibs.2010.08.004] [PMID: 20888775]

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