Kinesin Family Deregulation Coordinated by Bromodomain Protein ANCCA and Histone Methyltransferase MLL for Breast Cancer Cell Growth, Survival, and Tamoxifen Resistance

Abstract

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. Implications These 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.

Positive expression of KIF20A indicates poor prognosis of glioma patients

“…It was first identified to function in the dynamics of the Golgi apparatus through interaction with the Rab6A/B GTPase. Moreover, it has been reported that KIF20A is overexpressed in melanoma,11 bladder cancer,10,12 breast cancer,13–15 and pancreatic cancer 16. Knockdown of KIF20A in pancreatic cancer cells can significantly inhibit cell proliferation,17,18 indicating the significance of its overexpression in human cancers.…”

Increased KIF15 Expression Predicts a Poor Prognosis in Patients with Lung Adenocarcinoma

“…KIF15 interacts with TPX2 to cross-link and slide between two microtubules, leading to centrosome separation during bipolar spindle assembly [13]. It has been reported that KIF15 is induced by estrogen and that its upregulation, together with ANCCA that is also induced by estrogen, is associated with breast cancer cell growth, survival, and resistance to tamoxifen [14]. Recently, KIF15 was found to be overexpressed in pancreatic cancer, where it promotes tumor cell proliferation via the MEK-ERK signaling pathway [15].…”

Chromokinesins in Genome Maintenance and Cancer

“…Cross-species comparative genomics analysis of progression from pre-invasive ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) in breast revealed 16 genes with concomitant genomic alterations, including KIF4A, that may be involved in tumorigenesis and in the processes of invasion and progression of disease [ 56 ]. These observations were further supported by the fi nding that elevated levels of Kif4A, Kif15, Kif20A, and Kif23 correlate with that of ANCCA (AAA nuclear co-regulator cancer-associated) in estrogen receptor (ER)-positive breast cancer cells with poor relapse-free survival of patients with ER-positive and tamoxifen-resistant breast cancer [ 65 ]. Furthermore, treatment of lung cancer cells with small interfering RNAs against KIF4A suppressed growth of these cells [ 57 ].…”