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

June X Zou, Zhijian Duan, Junjian Wang, Alex Sokolov, Jianzhen Xu, Christopher Z. Chen, Jian-Jian Li, Hongwu Chen

Research output: Contribution to journalArticle

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Abstract

UNLABELLED: 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, whereas suppresses the expression of seven 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 downregulation of kinesins by estrogen. Its overexpression drives estrogen-independent upregulation of specific kinesins. Mechanistically, ANCCA (AAA nuclear coregulator cancer associated) 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 patients with ER-positive breast cancer. 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.

Original languageEnglish (US)
Pages (from-to)539-549
Number of pages11
JournalMolecular cancer research : MCR
Volume12
Issue number4
DOIs
StatePublished - Apr 1 2014

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Kinesin
Tamoxifen
Nuclear Proteins
Cell Survival
Breast Neoplasms
Growth
Neoplasms
Estrogens
Estrogen Receptors
histone methyltransferase
Up-Regulation
Second Primary Neoplasms
Methylation
Transcriptional Activation
Genes
Chromatin
Down-Regulation
Cell Proliferation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kinesin family deregulation coordinated by bromodomain protein ANCCA and histone methyltransferase MLL for breast cancer cell growth, survival, and tamoxifen resistance. / Zou, June X; Duan, Zhijian; Wang, Junjian; Sokolov, Alex; Xu, Jianzhen; Chen, Christopher Z.; Li, Jian-Jian; Chen, Hongwu.

In: Molecular cancer research : MCR, Vol. 12, No. 4, 01.04.2014, p. 539-549.

Research output: Contribution to journalArticle

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abstract = "UNLABELLED: 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, whereas suppresses the expression of seven 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 downregulation of kinesins by estrogen. Its overexpression drives estrogen-independent upregulation of specific kinesins. Mechanistically, ANCCA (AAA nuclear coregulator cancer associated) 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 patients with ER-positive breast cancer. 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.",
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AU - Zou, June X

AU - Duan, Zhijian

AU - Wang, Junjian

AU - Sokolov, Alex

AU - Xu, Jianzhen

AU - Chen, Christopher Z.

AU - Li, Jian-Jian

AU - Chen, Hongwu

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N2 - UNLABELLED: 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, whereas suppresses the expression of seven 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 downregulation of kinesins by estrogen. Its overexpression drives estrogen-independent upregulation of specific kinesins. Mechanistically, ANCCA (AAA nuclear coregulator cancer associated) 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 patients with ER-positive breast cancer. 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.

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