Histone acetyltransferase Hbo1 destabilizes estrogen receptor α by ubiquitination and modulates proliferation of breast cancers

Abstract

The estrogen receptor ( ER) is a key molecule for growth of breast cancers. It has been a successful target for treatment of breast cancers. Elucidation of the ER expression mechanism is of importance for designing therapeutics for ER‐positive breast cancers. However, the detailed mechanism of ER stability is still unclear. Here, we report that histone acetyltransferase Hbo1 promotes destabilization of estrogen receptor α ( ERα) in breast cancers through lysine 48‐linked ubiquitination. The acetyltransferase activity of Hbo1 is linked to its activity for ERα ubiquitination. Depletion of Hbo1 and anti‐estrogen treatment displayed a potent growth suppression of breast cancer cell line. Hbo1 modulated transcription by ERα. Mutually exclusive expression of Hbo1 and ERα was observed in roughly half of the human breast tumors examined in the present study. Modulation of ER stability by Hbo1 in breast cancers may provide a novel therapeutic possibility.

Abstract

Approximately two‐thirds of breast cancers are dependent for proliferation and they respond to anti‐hormone therapy. However, some breast cancers show resistance against anti‐hormone therapy and recurrence occurs. The molecular mechanism of the resistance is largely unknown. Iizuka et al. uncovered a novel regulation of stability of estrogen receptor alpha, a central player for the estrogen‐dependent growth of breast cancers. They found that DNA replication‐associated histone acetyltransferase, Hbo1, promotes degradation of estrogen receptor alpha by ubiquitination.