MED28 and forkhead box M1 (FOXM1) mediate matrix metalloproteinase 2 (MMP2)‐dependent cellular migration in human nonsmall cell lung cancer (NSCLC) cells

Abstract

Non‐small‐cell lung cancer (NSCLC) accounts for the majority of the lung cancer cases that have become a leading cause of cancer deaths worldwide. Overexpression of transcription factor forkhead box M1 (FOXM1) is involved in the inauspicious development of several types of cancer, including lung tumor aggressiveness. Our laboratory has previously found that MED28, a Mediator subunit for transcriptional activation, modulates cell growth, epithelial‐mesenchymal transition, migration, and invasion in human breast cancer cells. The objective of the current study is to investigate the potential role of MED28 and FOXM1 in NSCLC. In addition to A549 and PC9 cells, we also used a doxycycline‐inducible system to generate FOXM1‐overexpressed A549‐DN cells, and we explored the connection of MED28 with FOXM1 and their effect on migration. Herein, we report that the increased expression levels of both MED28 and FOXM1 elevated the expression of matrix metalloproteinase 2 (MMP2), a metastasis marker, which enhanced cell migration and matrigel invasion of NSCLC cells. Furthermore, MED28 interacted with FOXM1, and both exhibited a mutual effect on the expression and subcellular localization. Moreover, MED28 small interfering RNA‐mediated MMP2 gene suppression could be attenuated by inducible expression of a constitutively active form of FOXM1, which consequently restored the migration and invasion ability of NSCLC cells. Our data indicate that MED28 interacts with FOXM1, and each affects the expression and localization of the other, and, more importantly, both regulate MMP2‐dependent migration and invasion in human lung cancer cells.

RCOR1 directly binds to MED28 and weakens its inducing effect on cancer stem cell‐like activity of oral cavity squamous cell carcinoma cells

“…Its overexpression could be induced by E2F transcription factor 1, nuclear respiratory factor 1, E‐26 transforming sequence 1, and CCAAT/enhancer‐binding protein β and reduces the duration of interphase and mitosis, thereby leading to genomic instability and aneuploidy 13 . Its dysregulation has been reported in multiple cancers, such as breast cancer, 14,15 colorectal cancer, 16 and non‐small cell lung cancer (NSCLC) 17 . As essential transcriptional coactivators, mediators are supposed to regulate a series of gene expression and signaling pathways.…”

“…It augments the Wnt/β‐catenin signaling pathway in colorectal cancer cells by negatively regulating HMG box‐containing protein 1 (HBP1) expression 16 . In NSCLC cells, MED28 interacts with FOXM1, thereby modulating MMP2‐dependent cellular migration 17 …”

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

“…The FOXM1 transcription factor, mainly expressed in the proliferative cells, is a member of the Forkhead box family of transcription factors. Recent studies have demonstrated that FOXM1 is frequently overexpressed in different kinds of cancers, including PCa, and is con rmed to be highly correlated with the proliferation and metastasis of many cancers [4][5][6][7][8]. Moreover, several studies indicated that FOXM1 overexpression conferred acquired chemotherapy tolerance through the regulation of many genes, including ATP-binding cassette genes [9][10], DNA damage repair genes [11], apoptosis-associated genes [12], cancer stem cell-related genes [13][14], and so on.…”

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

“…FOXM1, a transcription factor mainly expressed in proliferative cells, is part of the Forkhead box family of transcription factors. Recent studies indicate FOXM1 is commonly overexpressed in many kinds of cancers, including PCa, and its expression is highly correlated with cancer proliferation and metastasis [4][5][6][7][8]. Several studies suggest FOXM1 overexpression confers acquired chemotherapy tolerance through the regulation of numerous genes, including ATP-binding cassette genes [9][10], DNA damage repair genes [11], apoptosis-associated genes [12], cancer stem cell-related genes [13][14].…”