MOF negatively regulates estrogen receptor α signaling via CUL4B-mediated protein degradation in breast cancer

Estrogen receptor alpha (ER alpha) is the dominant tumorigenesis driver in breast cancer (BC), and ER alpha-positive BC (ER alpha+ BC) accounts for more than two-thirds of BC cases. MOF (males absent on the first) is a highly conserved histone acetyltransferase that acetylates lysine 16 of histone H4 (H4K16) and several non-histone proteins. Unbalanced expression of MOF has been identified, and high MOF expression predicted a favorable prognosis in BC. However, the association of MOF with ER alpha and the regulatory mechanisms of MOF in ER alpha signaling remain elusive. Our study revealed that the expression of MOF is negatively correlated with that of ER alpha in BC. In ER alpha+ BC cells, MOF overexpression downregulated the protein abundance of ER alpha in both cytoplasm and nucleus, thus attenuating ER alpha-mediated transactivation as well as cellular proliferation and in vivo tumorigenicity of BC cells. MOF promoted ER alpha protein degradation through CUL4B-mediated ubiquitin-proteasome pathway and induced HSP90 hyperacetylation that led to the loss of chaperone protection of HSP90 to ER alpha. We also revealed that suppression of MOF restored ER alpha expression and increased the sensitivity of ER alpha-negative BC cells to tamoxifen treatment. These results provide a new insight into the tumor-suppressive role of MOF in BC via negatively regulating ER alpha action, suggesting that MOF might be a potential therapeutic target for BC.