ABCG2 Localizes to the Nucleus and Modulates CDH1 Expression in Lung Cancer Cells

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.

Optimization of Storage Temperature for Retention of Undifferentiated Cell Character of Cultured Human Epidermal Cell Sheets

“…This was less prominent in CES in our two-week storage study 18 , which could be due to the use of a different antibody clone (H-70 compared to BXP-21 used here). To our knowledge, nuclear expression of this transporter in CES has not been previously reported, though ABCG2 has been shown to act as a nuclear transcription factor in the transcription of E-cadherin in lung cancer cells 43 . Alternatively, nuclear membrane localization of ABCG2 would suggest a nuclear efflux role for this transporter in epidermal keratinocytes, as has been shown in other cell types 44 – 46 .…”

ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling

“…Interestingly, ABCG2 can bind to the E-box promoter region of CDH1 (E-cadherin) regulating E-cadherin expression [46]. Low levels of ABCG2 that was detected in resections of primary tumors therefore can be considered as part of the dedifferentiation process leading to low E-cadherin levels and loosened tight junction interactions facilitating cellular migration that is necessary for tumor progression.…”

SOX4 contributes to the progression of cervical cancer and the resistance to the chemotherapeutic drug through ABCG2

“… 17 , 18 , 19 , 20 , 21 There are some reports that ABCG2 located on the membranes of mitochondria, 22 in perinuclear region 23 or in nuclear as a transcription regulator to modulate the metastasis in lung cancer. 24 In addition, ABCG2 is also used as a marker for cancer stem cells or cancer-initiating cells in various human cancers. 25 , 26 …”