Capping Protein Regulator and Myosin 1 Linker 3 Is Required for Tumor Metastasis
Capping Protein Regulator and Myosin 1 Linker 3 Is Required for Tumor Metastasis
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DOI：
10.1158/1541-7786
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Xiaojing Ma
中科院分区：
文献类型：
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作者：
Han Wang;Chao Wang;Guang Peng;Doudou Yu;Xin-Gang Cui;Yinhao Sun;Xiaojing Ma
Metastasis accounts for 90% of deaths caused by solid tumors, but the multitude of mechanisms underlying tumor metastasis remains poorly understood. CARMIL1 and 2 proteins are capping protein (CP) interactants and multidomain regulators of actin-based mobility. However, CARMIL3's function has not been explored. Through bioinformatic metadata analysis, we find that high CARMIL3 expression correlates with poor survival of patients with breast and prostate cancer. Functional studies in murine and xenograft tumor models by targeted diminution of CARMIL3 expression or forced expression demonstrate that CARMIL3 is vitally important for tumor metastasis, especially for metastatic colonization. Consistent with a predominantly cell-intrinsic mode of action, CARMIL3 is also crucial for tumor cell migration and invasion in vitro. Coimmunoprecipitation coupled with mass spectrometric analyses identifies a group of CARMIL3-interacting proteins, including capping protein, that are involved in actin cytoskeletal organization, which is required for cell polarization and focal adhesion formation. Moreover, molecular pathway enrichment analysis reveals that lack of CARMIL3 leads to loss of cell adhesions and low CARMIL3 expression in breast cancer patient specimens is implicated in epithelial-mesenchymal transition. We also find that CARMIL3 sustains adherens junction between tumor cells. This is accomplished by CARMIL3 maintaining E-cadherin transcription downstream of HDACs through inhibiting ZEB2 protein level, also via protecting β-catenin from ubiquitination-mediated degradation initiated by the destruction complex. IMPLICATIONS: This study uncovers CARMIL3 as a novel and critical regulator of metastatic progression of cancers and suggests therapeutic potentials to target CARMIL3.
