Kinesin family deregulation coordinated by bromodomain protein ANCCA and histone methyltransferase MLL for breast cancer cell growth survival and tamoxifen resistance

摘要

Kinesins are a superfamily of motor proteins and often deregulated in different cancers. However, the mechanism of their deregulation has been poorly understood. Through examining kinesin gene family expression in estrogen receptor (ER)-positive breast cancer cells, we found that estrogen stimulation of cancer cell proliferation involves a concerted regulation of specific kinesins. Estrogen strongly induces expression of 19 kinesin genes such as Kif4A/4B, Kif5A/5B, Kif10, Kif11, Kif15, Kif18A/18B, Kif20A/20B, Kif21, Kif23, Kif24, Kif25 and KifC1 while suppresses the expression of 7 others including Kif1A, Kif1C, Kif7 and KifC3. Interestingly, the bromodomain protein ANCCA/ATAD2, previously shown to be an estrogen-induced chromatin regulator, plays a crucial role in the up- and down-regulation of kinesins by estrogen. Its overexpression drives estrogen-independent up-regulation of specific kinesins. Mechanistically, ANCCA mediates E2-dependent recruitment of E2F and MLL1 histone methyltransferase at kinesin gene promoters for gene activation associated H3K4me3 methylation. Importantly, elevated levels of Kif4A, Kif15, Kif20A and Kif23 correlate with that of ANCCA in the tumors and with poor relapse-free survival of ER-positive breast cancer patients. Their knockdown strongly impeded proliferation and induced apoptosis of both tamoxifen-sensitive and -resistant cancer cells. Together, the study reveals ANCCA as a key mediator of kinesin family deregulation in breast cancer and the crucial role of multiple kinesins in growth and survival of the tumor cells.ImplicationsThese findings support the development of novel inhibitors of cancer-associated kinesins and their regulator ANCCA for effective treatment of cancers including tamoxifen-resistant breast cancers.