The ZEB1/miR-200 feedback loop controls Notch signalling in cancer cells

Abstract

Notch signalling is important for development and tissue homeostasis and activated in many human cancers. Nevertheless, mutations in Notch pathway components are rare in solid tumours. ZEB1 is an activator of an epithelial–mesenchymal transition (EMT) and has crucial roles in tumour progression towards metastasis. ZEB1 and miR‐200 family members repress expression of each other in a reciprocal feedback loop. Since miR‐200 members target stem cell factors, ZEB1 indirectly induces stemness maintenance and associated drug resistance. Here, we link ZEB1 and its cancer promoting properties to Notch activation. We show that miR‐200 members target Notch pathway components, such as Jagged1 (Jag1) and the mastermind‐like coactivators Maml2 and Maml3, thereby mediating enhanced Notch activation by ZEB1. We further detected a coordinated upregulation of Jag1 and ZEB1, associated with reduced miR‐200 expression in two aggressive types of human cancer, pancreatic adenocarcinoma and basal type of breast cancer. These findings explain increased Notch signalling in some types of cancers, where mutations in Notch pathway genes are rare. Moreover, they indicate an additional way how ZEB1 exerts its tumour progressing functions.

ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma

“…34 Significantly, relevant molecular targets of the miR-200/ZEB1 loop include the stem cell-associated factors BMI1, SOX2, KLF4, 14 and Notch signaling pathway. 35 Summarizing, we demonstrated for the first time that absence or severe dowregulation of E-cadherin associated with ZEB1 overexpression is characteristic of undifferentiated endometrial carcinomas. As these alterations are very infrequently seen in grade 3 endometrioid endometrial carcinomas and can be evaluated by immunohistochemistry, our results have important implications for the differential diagnosis of both types of tumors, which show different prognosis.…”

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…In one of the earliest studies of pancreatic and colon cancers, Wellner et al discovered that Zeb1 promotes tumorigenicity by repressing stemness-inhibiting miRNAs [156]. In follow up investigations, they determined that the miR-200 family targets Notch pathway components, such as Jagged1, to mediate enhanced Notch activation of Zeb1 in two aggressive types of human solid tumors [157]. MiR-200 essentially counteracts classical EMT properties such as cell motility, and suppresses translation of stem cells factors, including Bmi1.…”

An integrated transcriptional regulatory circuit that reinforces the breast cancer stem cell state

“…Depletion of Zeb1 and Zeb2 decreases the proportion of CSCs in the population of transformed ER-Src cells (11), and Zeb1 and Zeb2 repress the expression of miR-200 family members (24). As the miRNAs involved in CSC function are coordinately down-regulated in CSC cells, we examined whether Zeb1 and Zeb2 affect the expression of the CSC-regulating miRNAs (Fig.…”

“…In addition, miR-200 affects CSC function by directly targeting Bmi1 (9,20) and Suz12 (11), which, respectively, are components of the PRC1 and PRC2 polycomb complexes that repress transcription. Targets of miR-200 also include proteins involved in secretion (21), cell motility, and anoikis resistance (22), SIRT1 (23), and the Notch pathway (24), and it has been suggested that the stem cell factor Klf4 is also a target (20).…”