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Enhancement of E-cadherin expression and processing and driving of cancer cell metastasis by ARID1A deficiency

Oncogene volume 40, pages 5468–5481 (2021)Cite this article

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Abstract

The ARID1A gene, which encodes a subunit of the SWI/SNF chromatin remodeling complex, has been found to be frequently mutated in many human cancer types. However, the function and mechanism of ARID1A in cancer metastasis are still unclear. Here, we show that knockdown of ARID1A increases the ability of breast cancer cells to proliferate, migrate, invade, and metastasize in vivo. The ARID1A-related SWI/SNF complex binds to the second exon of CDH1 and negatively modulates the expression of E-cadherin/CDH1 by recruiting the transcriptional repressor ZEB2 to the CDH1 promoter and excluding the presence of RNA polymerase II. The silencing of CDH1 attenuated the migration, invasion, and metastasis of breast cancer cells in which ARID1A was silenced. ARID1A depletion increased the intracellular enzymatic processing of E-cadherin and the production of C-terminal fragment 2 (CTF2) of E-cadherin, which stabilized β-catenin by competing for binding to the phosphorylation and degradation complex of β-catenin. The matrix metalloproteinase inhibitor GM6001 inhibited the production of CTF2. In zebrafish and nude mice, ARID1A silencing or CTF2 overexpression activated β-catenin signaling and promoted migration/invasion and metastasis of cancer cells in vivo. The inhibitors GM6001, BB94, and ICG-001 suppressed the migration and invasion of cancer cells with ARID1A-deficiency. Our findings provide novel insights into the mechanism of ARID1A metastasis and offer a scientific basis for targeted therapy of ARID1A-deficient cancer cells.

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Fig. 1: Loss of ARID1A promotes tumor cell migration, invasion, and metastasis.
Fig. 2: ARID1A-associated SWI/SNF complex regulates CDH1 (E-cadherin) transcription in a negative fashion.
Fig. 3: Loss of ARID1A associates with increased intracellular digestion of E-cad.
Fig. 4: Loss of ARID1A and expression of E-cad/CTFs increases β–catenin and epithelial to mesenchymal transition (EMT) markers.
Fig. 5: E-cad/CTF2 stabilizes β−catenin by competitive binding with the phosphorylation and degradation complex of β−catenin.
Fig. 6: ARID1A-deficiency and upregulation of E-cad/CTF2 activate β–catenin downstream signaling.
Fig. 7: CTF2 promotes migration, invasion, and metastasis of BC cells with ARID1A-deficiency.

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Acknowledgements

We acknowledge Yi-Yuan Ren, Jia-Hui Li, and Xiao-Qiang Chai for their helps in experiments. The work was supported by the National Natural Science Foundation of China (NSFC) (81572833, 22074020), Chinese National Key Program on Basic Research Grant (2011CB910702, 2013CB911202), and the Natural Science Foundation of Shanghai (14ZR1402100).

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  1. These authors contributed equally: Jie Wang, Hai-Bo Yan.

Authors and Affiliations

  1. Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China

    Jie Wang, Hai-Bo Yan, Qian Zhang, Wei-Yan Liu, Ying-Hua Jiang, Peng-Yuan Yang & Feng Liu

  2. Institutes of Brain Science, Fudan University, Shanghai, China

    Gang Peng

  3. Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Fei-Zhen Wu, Peng-Yuan Yang & Feng Liu

  4. Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Xin Liu

  5. Department of Chemistry, Fudan University, Shanghai, China

    Peng-Yuan Yang

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Contributions

FL and PYY conceived the study. JW, HBY, QZ, XL, GP, FZW, and YHJ performed the experiments. WYL contributed to the clinical samples. FL wrote the manuscript. All authors reviewed and approved the manuscript for publication.

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Correspondence to Peng-Yuan Yang or Feng Liu.

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Wang, J., Yan, HB., Zhang, Q. et al. Enhancement of E-cadherin expression and processing and driving of cancer cell metastasis by ARID1A deficiency. Oncogene 40, 5468–5481 (2021). https://doi.org/10.1038/s41388-021-01930-2

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