YY1 Oligomerization Is Regulated by Its OPB Domain and Competes with Its Regulation of Oncoproteins

Simple Summary YY1 regulates various cancer-related genes and activates key oncoproteins. In this study, we discovered that the oncoprotein binding (OPB) domain of YY1 is both necessary and stimulatory to its oligomerization. The hydrophobic residues, especially F219, in the OPB are essential to YY1 intermolecular interaction. Strikingly, the mutations of the hydrophobic residues showed better ability than wild-type YY1 in promote breast cancer cell proliferation and migration. Our further study revealed that YY1 proteins with mutated hydrophobic residues in the OPB domain showed improved binding affinity to EZH2. Overall, our data support the model of a mutually exclusive process between oligomerization of YY1 and its regulation of the oncoproteins EZH2, AKT and MDM2. Yin Yang 1 (YY1) plays an oncogenic role through regulating the expression of various cancer-related genes and activating key oncoproteins. Previous research reported that YY1 protein formed dimers or oligomers without definite biological implications. In this study, we first demonstrated the oncoprotein binding (OPB) and zinc finger (ZF) domains of YY1 as the regions involved in its intermolecular interactions. ZFs are well-known for protein dimerization, so we focused on the OPB domain. After mutating three hydrophobic residues in the OPB to alanines, we discovered that YY1(F219A) and YY1(3A), three residues simultaneously replaced by alanines, were defective of intermolecular interaction. Meanwhile, the OPB peptide could robustly facilitate YY1 protein oligomerization. When expressed in breast cancer cells with concurrent endogenous YY1 knockdown, YY1(F219A) and (3A) mutants showed better capacity than wt in promoting cell proliferation and migration, while their interactions with EZH2, AKT and MDM2 showed differential alterations, especially with improved EZH2 binding affinity. Our study revealed a crucial role of the OPB domain in facilitating YY1 oligomerization and suggested a mutually exclusive regulation between YY1-mediated enhancer formation and its activities in promoting oncoproteins.