Characterization of YY1 OPB Peptide for its Anticancer Activity

Author(s): Yige Qi, Ting Yan, Lu Chen, Qiang Zhang, Weishu Wang, Xu Han, Dangdang Li, Jinming Shi, Guangchao Sui*

Journal Name: Current Cancer Drug Targets

Volume 19 , Issue 6 , 2019

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Graphical Abstract:


Background: The oncoprotein binding (OPB) domain of Yin Yang 1 (YY1) consists of 26 amino acids between G201 and S226, and is involved in YY1 interaction with multiple oncogene products, including MDM2, AKT, EZH2 and E1A. Through the OPB domain, YY1 promotes the oncogenic or proliferative regulation of these oncoproteins in cancer cells. We previously demonstrated that a peptide with the OPB sequence blocked YY1-AKT interaction and inhibited breast cancer cell proliferation.

Objective: In the current study, we characterized the OPB domain and determined a minimal region for peptide design to suppress cancer cells.

Methods: Using alanine-scan method, we identified that the amino acids at OPB C-terminal are essential to YY1 binding to AKT. Further studies suggested that serine and threonine residues, but not lysines, in OPB play a key role in YY1-AKT interaction. We generated GFP fusion expression vectors to express OPB peptides with serially deleted N-terminal and found that OPB1 (i.e. G201-S226) is cytoplasmic, but OPB2 (i.e. E206-S226), OPB3 (i.e. E206-S226) and control peptide were both nuclear and cytoplasmic.

Results: Both OPB1 and 2 inhibited breast cancer cell proliferation and migration, but OPB3 exhibited similar effects to control. OPB1 and 2 caused cell cycle arrest at G1 phase, increased p53 and p21 expression, and reduced AKT(S473) phosphorylation in MCF-7 cells, but not in MDA-MB-231 cells.

Conclusion: Overall, the serines and threonines of OPB are essential to YY1 binding to oncoproteins, and OPB peptide can be minimized to E206-S226 that maintain inhibitory activity to YY1- promoted cell proliferation.

Keywords: YY1, OPB peptide, protein interaction, inhibitory activity, anticancer activity, oncoproteins.

Zhang, Q.; Stovall, D.B.; Inoue, K.; Sui, G. The oncogenic role of Yin Yang 1. Crit. Rev. Oncog., 2011, 16, 163-197.
Zhang, Q.; Wan, M.; Shi, J.; Horita, D.A.; Miller, L.D.; Kute, T.E.; Kridel, S.J.; Kulik, G.; Sui, G. Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation. J. Mol. Cell Biol., 2016, 8, 232-243.
Sui, G. Affar el, B.; Shi, Y.; Brignone, C.; Wall, N.R.; Yin, P.; Donohoe, M.; Luke, M.P.; Calvo, D.; Grossman, S.R.; Shi, Y. Yin Yang. 1 is a negative regulator of p53. Cell, 2004, 117, 859-872.
Gronroos, E.; Terentiev, A.A.; Punga, T.; Ericsson, J. YY1 inhibits the activation of the p53 tumor suppressor in response to genotoxic stress. Proc. Natl. Acad. Sci. USA, 2004, 101, 12165-12170.
Hernandez-Munoz, I.; Taghavi, P.; Kuijl, C.; Neefjes, J.; van Lohuizen, M. Association of BMI1 with polycomb bodies is dynamic and requires PRC2/EZH2 and the maintenance DNA methyltransferase DNMT1. Mol. Cell. Biol., 2005, 25, 11047-11058.
Wilkinson, F.; Park, K.; Atchison, M.L. Polycomb recruitment to DNA in vivo by the YY1 REPO domain. Proc. Natl. Acad. Sci. USA, 2006, 103, 19296-19301.
Wilkinson, F.; Pratt, H.; Atchison, M.L. PcG recruitment by the YY1 REPO domain can be mediated by Yaf2. J. Cell. Biochem., 2010, 109, 478-486.
Lee, J.S.; See, R.H.; Galvin, K.M.; Wang, J.; Shi, Y. Functional interactions between YY1 and adenovirus E1A. Nucleic Acids Res., 1995, 23, 925-931.
Lewis, B.A.; Tullis, G.; Seto, E.; Horikoshi, N.; Weinmann, R.; Shenk, T. Adenovirus E1A proteins interact with the cellular YY1 transcription factor. J. Virol., 1995, 69, 1628-1636.
Zhou, Q.; Engel, D.A. Adenovirus E1A243 disrupts the ATF/CREB-YY1 complex at the mouse c-fos promoter. J. Virol., 1995, 69, 7402-7409.
Cunningham, B.C.; Wells, J.A. High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Science, 1989, 244, 1081-1085.
Trinh, R.; Gurbaxani, B.; Morrison, S.L.; Seyfzadeh, M. Optimization of codon pair use within the (GGGGS)3 linker sequence results in enhanced protein expression. Mol. Immunol., 2004, 40, 717-722.
Runnebaum, I.B.; Nagarajan, M.; Bowman, M.; Soto, D.; Sukumar, S. Mutations in p53 as potential molecular markers for human breast cancer. Proc. Natl. Acad. Sci. USA, 1991, 88, 10657-10661.
Shen, Y.; Maupetit, J.; Derreumaux, P.; Tuffery, P. Improved PEP-FOLD approach for peptide and miniprotein structure prediction. J. Chem. Theory Comput., 2014, 10, 4745-4758.
Yao, Y.L.; Yang, W.M.; Seto, E. Regulation of transcription factor YY1 by acetylation and deacetylation. Mol. Cell. Biol., 2001, 21, 5979-5991.
Deng, Z.; Wan, M.; Sui, G. PIASy-mediated sumoylation of Yin Yang 1 depends on their interaction but not the RING finger. Mol. Cell. Biol., 2007, 27, 3780-3792.
Zhang, W.J.; Wu, X.N.; Shi, T.T.; Xu, H.T.; Yi, J.; Shen, H.F.; Huang, M.F.; Shu, X.Y.; Wang, F.F.; Peng, B.L.; Xiao, R.Q.; Gao, W.W.; Ding, J.C.; Liu, W. Regulation of transcription factor Yin Yang 1 by SET7/9-mediated lysine methylation. Sci. Rep., 2016, 6, 21718.
Rizkallah, R.; Hurt, M.M. Regulation of the transcription factor YY1 in mitosis through phosphorylation of its DNA-binding domain. Mol. Biol. Cell, 2009, 20, 4766-4776.
Zheng, H.; Chu, J.; Zeng, Y.; Loh, H.H.; Law, P.Y. Yin Yang 1 phosphorylation contributes to the differential effects of mu-opioid receptor agonists on microRNA-190 expression. J. Biol. Chem., 2010, 285, 21994-22002.
Hiromura, M.; Choi, C.H.; Sabourin, N.A.; Jones, H.; Bachvarov, D.; Usheva, A. YY1 is regulated by O-linked N-acetylglucosaminylation (O-glcNAcylation). J. Biol. Chem., 2003, 278, 14046-14052.
Jokela, T.A.; Makkonen, K.M.; Oikari, S.; Karna, R.; Koli, E.; Hart, G.W.; Tammi, R.H.; Carlberg, C.; Tammi, M.I. Cellular content of UDP-N-Acetylhexosamines controls hyaluronan synthase 2 expression and correlates with O-GlcNAc modification of transcription factors YY1 and SP1. J. Biol. Chem., 2011, 286, 33632-33640.
Ozcan, S.; Andrali, S.S.; Cantrell, J.E. Modulation of transcription factor function by O-GlcNAc modification. Biochim. Biophys. Acta, 2010, 1799, 353-364.
Griesenbeck, J.; Ziegler, M.; Tomilin, N.; Schweiger, M.; Oei, S.L. Stimulation of the catalytic activity of poly(ADP-ribosyl) transferase by transcription factor Yin Yang 1. FEBS Lett., 1999, 443, 20-24.
Palko, L.; Bass, H.W.; Beyrouthy, M.J.; Hurt, M.M. The Yin Yang-1 (YY1) protein undergoes a DNA-replication-associated switch in localization from the cytoplasm to the nucleus at the onset of S phase. J. Cell Sci., 2004, 117, 465-476.

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Article Details

Year: 2019
Page: [504 - 511]
Pages: 8
DOI: 10.2174/1568009618666181031153151
Price: $65

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