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.