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Microbiology and Immunology

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Capping Protein Regulator and Myosin 1 Linker 3 Is Required for Tumor Metastasis.

TitleCapping Protein Regulator and Myosin 1 Linker 3 Is Required for Tumor Metastasis.
Publication TypeJournal Article
Year of Publication2020
AuthorsWang H, Wang C, Peng G, Yu D, Cui X-G, Sun Y-H, Ma X
JournalMol Cancer Res
Volume18
Issue2
Pagination240-252
Date Published2020 02
ISSN1557-3125
Abstract

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 . 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.

DOI10.1158/1541-7786.MCR-19-0722
Alternate JournalMol Cancer Res
PubMed ID31694931

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