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Acetylation of ACAP4 regulates CCL18-elicited breast cancer cell migration and invasion Free
Xiaoyu Song 1,3,† , Wei Liu 1,3,† , Xiao Yuan 1,4 , Jiying Jiang 1,3 , Wanjuan Wang 2 , McKay Mullen 3 , Xuannv Zhao 1 , Yin Zhang 1,2 , Fusheng Liu 1,2 , Shihao Du 1,2 , Adeel Rehman 1 , Ruijun Tian 4 , Jian Li 3 , Andra Frost 5 , Zhenwei Song 1 , Hadiyah-Nicole Green 3 , Calmour Henry 3 , Xing Liu 1,3,* , Xia Ding 2,3,* , Dongmei 1,* , and Xuebiao Yao 1,*
1 Anhui Key Laboratory for Cellular Dynamics & Chemical Biology, Hefei National Science Center for Physical Sciences at Nanoscale, CAS Center of Excellence in Molecular Cell Sciences, University of Science & Technology of China, Hefei 230027, China
2 School of Basic Medical Sciences, Beijing University of Chinese Medicine, Beijing 100029, China
3 Keck Center for Cellular Dynamics & Department of Physiology, Morehouse School of Medicine, Atlanta, GA 30310, USA
4 Department of Chemistry, Southern University of Science & Technology, Shenzhen 518055, China
5 Department of Pathology, University of Alabama School of Medicine, Birmingham, AL 35294, USA
These authors contributed equally to this work.
*Correspondence to:* Correspondence to: Xuebiao Yao, E-mail: yaoxb@ustc.edu.cn; Xia Ding, E-mail: dingx@bucm.edu.cn; Dongmei Wang, E-mail: wangdm@ustc.edu.cn; Xing Liu,E-mail: xing1017@ustc.edu.cn
J Mol Cell Biol, Volume 10, Issue 6, December 2018, Pages 559-572  https://doi.org/10.1093/jmcb/mjy058
Keyword: cell migration, acetylation, ACAP4, CCL18, PCAF, ARF6

Tumor metastasis represents the main causes of cancer-related death. Our recent study showed that chemokine CCL18 secreted from tumor-associated macrophages regulates breast tumor metastasis, but the underlying mechanisms remain less clear. Here, we show that ARF6 GTPase-activating protein ACAP4 regulates CCL18-elicited breast cancer cell migration via the acetyltransferase PCAF-mediated acetylation. CCL18 stimulation elicited breast cancer cell migration and invasion via PCAF-dependent acetylation. ACAP4 physically interacts with PCAF and is a cognate substrate of PCAF during CCL18 stimulation. The acetylation site of ACAP4 by PCAF was mapped to Lys311 by mass spectrometric analyses. Importantly, dynamic acetylation of ACAP4 is essential for CCL18-induced breast cancer cell migration and invasion, as overexpression of the persistent acetylation-mimicking or non-acetylatable ACAP4 mutant blocked CCL18-elicited cell migration and invasion. Mechanistically, the acetylation of ACAP4 at Lys311 reduced the lipid-binding activity of ACAP4 to ensure a robust and dynamic cycling of ARF6–ACAP4 complex with plasma membrane in response to CCL18 stimulation. Thus, these results present a previously undefined mechanism by which CCL18-elicited acetylation of the PH domain controls dynamic interaction between ACAP4 and plasma membrane during breast cancer cell migration and invasion.