ZEB1 induces EPB41L5 in the cancer mesenchymal program that drives ARF6-based invasion, metastasis and drug resistance

Abstract

Onset of the cancer mesenchymal program is closely associated with cancer malignancy and drug resistance. Among the different epithelial–mesenchymal transition (EMT)-associated transcriptional factors, ZEB1 has a key role in inducing the mesenchymal phenotypes and stem cell-like properties of different breast cancer cells. ARF6 and its effector AMAP1 are frequently overexpressed in breast cancer cells, and promote invasion, metastasis and drug resistance. EPB41L5 is induced during EMT, and mediates the disruption of E-cadherin-based cell–cell adhesion and the promotion of focal adhesion dynamics. Here we show that EPB41L5 is an integral component of the ARF6-based pathway, which is induced by ZEB1. We found that EPB41L5 is expressed at high levels in malignant breast cancer cells and binds to AMAP1. ZEB1 induced EPB41L5 both in cancer cells and normal cells. This relationship was recaptured with The Cancer Genome Atlas RNASeq data set, and correlated with the poor outcome of the patients. In contrast, diversified events, such as tumor growth factor β1 stimulation, expression of SNAI1 and TP53 mutation, can each cause the induction of ZEB1 and EPB41L5, depending on the cellular context. Our results demonstrated that the ZEB1-EPB41L5 axis is at the core of the cancer mesenchymal program that drives ARF6-based invasion, metastasis and drug resistance of significant populations of primary breast cancers, and is tightly correlated with the poor outcomes of patients.

High expression of EPB41L5, an integral component of the Arf6-driven mesenchymal program, correlates with poor prognosis of squamous cell carcinoma of the tongue

“…Consistently, we have shown that ZEB1 is central in inducing EPB41L5 in breast cancer cells and renal cancer cells [16, 18]. However, analysis of The Cancer Genome Atlas (TCGA) RNA-Seq datasets on human primary tongue SCCs showed that ZEB1 mRNA levels do not statistically correlate with EPB41L5 mRNA levels (Fig.…”

“…We have previously shown that silencing of EPB41L5 in other types of cancers, such as breast cancer and renal cancer, drastically improves their drug-resistance [16, 18]. We hence examined whether the same is the case with SCC-9 cells.…”

“…Although many such studies primarily dealt with breast cancer, the acquisition of mesenchymal properties has also been highly implicated in the malignancy of HNSCC [5]. We previously showed that the small GTPase ARF6 and its effector AMAP1 are often overexpressed in different types of cancers, including breast cancer and renal cancer, and play pivotal roles in promoting invasion, metastasis, and drug resistance [6–18]. We have moreover shown that AMAP1 binds to EPB41L5 [18], which is normally induced during epithelial-mesenchymal transition (EMT) [11].…”

“…We previously showed that the small GTPase ARF6 and its effector AMAP1 are often overexpressed in different types of cancers, including breast cancer and renal cancer, and play pivotal roles in promoting invasion, metastasis, and drug resistance [6–18]. We have moreover shown that AMAP1 binds to EPB41L5 [18], which is normally induced during epithelial-mesenchymal transition (EMT) [11]. Thus, the ARF6-AMAP1-EPB41L5 pathway appears to be a cancer-specific pathway that is not expressed in cancer cells unless they undergo EMT-like changes.…”

“…Thus, the ARF6-AMAP1-EPB41L5 pathway appears to be a cancer-specific pathway that is not expressed in cancer cells unless they undergo EMT-like changes. The ARF6 pathway promotes β1 integrin recycling and the downregulation of E-cadherin, thus enhancing cell adhesion dynamics and motile phenotypes [10, 13, 18]. …”