Cav2.2-NFAT2-USP43 axis promotes invadopodia formation and breast cancer metastasis through cortactin stabilization

Ying Xue; Min Li; Jie Hu; Yuanlin Song; Wei Guo; Changhong Miao; Di Ge; Yingyong Hou; Xuefei Wang; Xingxu Huang; Tianshu Liu; Xiaoping Zhang; Qihong Huang

doi:10.1038/s41419-022-05174-0

Ca_v2.2-NFAT2-USP43 axis promotes invadopodia formation and breast cancer metastasis through cortactin stabilization

Cell Death Dis. 2022 Sep 22;13(9):812. doi: 10.1038/s41419-022-05174-0.

Authors

Ying Xue^#^{1

2}, Min Li^#^{1

2}, Jie Hu³, Yuanlin Song³, Wei Guo⁴, Changhong Miao^{1

5}, Di Ge⁶, Yingyong Hou⁷, Xuefei Wang⁸, Xingxu Huang⁹, Tianshu Liu^{1

10}, Xiaoping Zhang¹¹, Qihong Huang^{12

13

14}

Affiliations

¹ Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, PR China.
² Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, PR China.
³ Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, PR China.
⁴ Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, PR China.
⁵ Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, PR China.
⁶ Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, PR China.
⁷ Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, PR China.
⁸ Department of General Surgery/Gastric Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, PR China.
⁹ School of Life Science and Technology, ShanghaiTech University, Shanghai, PR China.
¹⁰ Department of Medicial Oncology, Zhongshan Hospital, Fudan University, Shanghai, PR China.
¹¹ The Institute of Intervention Vessel, Tongji University School of Medicine, Shanghai, PR China. zxpsibs@163.com.
¹² Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, PR China. qihong_huang@fudan.edu.cn.
¹³ Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, PR China. qihong_huang@fudan.edu.cn.
¹⁴ Shanghai Respiratory Research Institute, Shanghai, PR China. qihong_huang@fudan.edu.cn.

^# Contributed equally.

Abstract

Distant metastasis is the main cause of mortality in breast cancer patients. Using the breast cancer genomic data from The Cancer Genome Atlas (TCGA), we identified brain specific Ca_v2.2 as a critical regulator of metastasis. Ca_v2.2 expression is significantly upregulated in breast cancer and its higher expression is inversely correlated with survival suggesting a previously unappreciated role of Ca_v2.2 in breast cancer. Ca_v2.2 is required for breast cancer migration, invasion, and metastasis. Interestingly, Ca_v2.2 promotes invadopodia formation and extracellular matrix (ECM) degradation through the stabilization of invadopodia component cortactin in a proteosome-dependent manner. Moreover, deubiquitinating enzyme USP43 mediated the functions of Ca_v2.2 in cortactin stabilization, invadopodia formation, ECM degradation, and metastasis. Interestingly, Ca_v2.2 upregulates USP43 expression through NFAT2 dephosphorylation and nuclear localization. Our study uncovered a novel pathway that regulates cortactin expression and invadopodia formation in breast cancer metastasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms* / pathology
Calcium Channels, N-Type* / metabolism
Cell Line, Tumor
Cortactin / genetics
Cortactin / metabolism
Deubiquitinating Enzymes* / metabolism
Extracellular Matrix / metabolism
Female
Humans
NFATC Transcription Factors* / metabolism
Neoplasm Invasiveness
Podosomes* / metabolism

Substances

CACNA1B protein, human
Calcium Channels, N-Type
Cortactin
NFATC Transcription Factors
NFATC1 protein, human
Deubiquitinating Enzymes