Acetylation of ACAP4 regulates CCL18-elicited breast cancer cell migration and invasion
Acetylation of ACAP4 regulates CCL18-elicited breast cancer cell migration and invasion
复制标题
ACAP4 的乙酰化调节 CCL18 引发的乳腺癌细胞迁移和侵袭。
DOI：
10.1093/jmcb/mjy058
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发表时间：
2018-12-01
影响因子：
5.5
通讯作者：
Yao, Xuebiao
中科院分区：
文献类型：
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作者：
Song, Xiaoyu;Liu, Wei;Yao, Xuebiao
肿瘤转移是癌症相关死亡的主要原因。我们最近的研究表明，从肿瘤相关巨噬细胞分泌的趋化因子CCL 18调节乳腺肿瘤转移，但其潜在机制尚不清楚。在这里，我们表明，ARF 6 GTP酶激活蛋白ACAP 4调节CCL 18引起的乳腺癌细胞迁移通过乙酰转移酶PCAF介导的乙酰化。CCL 18刺激通过PCAF依赖的乙酰化引起乳腺癌细胞迁移和侵袭。ACAP 4与PCAF物理相互作用，并且在CCL 18刺激期间是PCAF的同源底物。通过质谱分析，PCAF对ACAP 4的乙酰化位点定位于Lys 311。重要的是，ACAP 4的动态乙酰化对于CCL 18诱导的乳腺癌细胞迁移和侵袭是必不可少的，因为持续乙酰化模拟或不可乙酰化的ACAP 4突变体的过表达阻断了CCL 18诱导的细胞迁移和侵袭。从机制上讲，ACAP 4在Lys 311处的乙酰化降低了ACAP 4的脂质结合活性，以确保ARF 6-ACAP 4复合物与质膜响应于CCL 18刺激的稳健和动态循环。因此，这些结果提出了一个以前未定义的机制，通过该机制，CCL 18引起的PH结构域的乙酰化控制乳腺癌细胞迁移和侵袭过程中ACAP 4和质膜之间的动态相互作用。
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.