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ABCG2 localizes to the nucleus and modulates CDH1 expression in lung cancer cells
Shu-Ching Liang1, Chih-Yung Yang2, Ju-Yu Tseng1
1Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
Abstract:
Breast cancer resistance protein [BCRP/ATP-binding cassette subfamily G member 2 (ABCG2)] is a member of the ATP-binding cassette transporter family. The presence of ABCG2 on the plasma membrane in many kinds of human cancer cells contributes to multidrug resistance during chemotherapy, and it has been used as the side population marker for identifying cancer stem cells in lung cancers. We report here that, in addition to the membranous form, ABCG2 proteins are also found inside the nucleus, where they bind to the E-box of CDH1 (E-cadherin) promoter and regulate transcription of this gene. Increased expression of ABCG2 causes an increase of E-cadherin and attenuates cell migration, whereas knockdown of ABCG2 downregulates E-cadherin and enhances cell motility. In mice, xenografted A549 cells that have less ABCG2 are more likely to metastasize from the subcutaneous inoculation site to the internal organs. However, for the cancer cells that have already entered the blood circulation, an increased level of ABCG2, and correspondingly increased E-cadherin, may facilitate circulating cancer cells to colonize at a distant site and form a metastatic tumor. We propose a novel role for nuclear ABCG2 that functions as a transcription regulator and participates in modulation of cancer metastasis.
Insights
Breast cancer resistance protein (BCRP/ABCG2) functions inside the nucleus to regulate E-cadherin, impacting cancer cell migration and metastasis. Its nuclear role offers new insights into cancer stem cell behavior and therapeutic resistance.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Breast cancer resistance protein (BCRP/ATP-binding cassette subfamily G member 2, ABCG2) is a key transporter implicated in multidrug resistance and cancer stem cell identification.
- ABCG2 is typically found on the plasma membrane of cancer cells, contributing to therapeutic challenges.
Purpose of the Study:
- To investigate the novel intracellular localization and function of ABCG2 beyond its role as a plasma membrane transporter.
- To elucidate the role of ABCG2 in regulating gene transcription and its impact on cancer cell behavior, specifically migration and metastasis.
Main Methods:
- Analysis of ABCG2 localization within cancer cells, including nuclear presence.
- Investigation of ABCG2 binding to the CDH1 (E-cadherin) promoter and its transcriptional regulatory activity.
- Experimental manipulation of ABCG2 expression (knockdown and overexpression) to assess effects on E-cadherin levels, cell migration, and metastasis in vitro and in vivo mouse models.
Main Results:
- ABCG2 is present not only on the plasma membrane but also within the nucleus of cancer cells.
- Nuclear ABCG2 directly binds to the E-box of the CDH1 (E-cadherin) promoter, regulating E-cadherin transcription.
- Increased ABCG2 expression elevates E-cadherin, reducing cell migration, while ABCG2 knockdown decreases E-cadherin and enhances motility.
- In vivo studies showed that reduced ABCG2 expression promoted metastasis, whereas increased ABCG2 and E-cadherin facilitated colonization of circulating tumor cells.
Conclusions:
- ABCG2 possesses a novel nuclear function as a transcription regulator, directly influencing E-cadherin expression.
- This nuclear role of ABCG2 significantly modulates cancer cell migration and metastasis, offering new perspectives on its involvement in cancer progression.
- Targeting nuclear ABCG2 may represent a potential therapeutic strategy to control cancer metastasis.
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