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MicroRNA-200 (miR-200) cluster regulation by achaete scute-like 2 (Ascl2): impact
on the epithelial-mesenchymal transition in colon cancer cells
#MMPMID25371200
Tian Y
; Pan Q
; Shang Y
; Zhu R
; Ye J
; Liu Y
; Zhong X
; Li S
; He Y
; Chen L
; Zhao J
; Chen W
; Peng Z
; Wang R
J Biol Chem
2014[Dec]; 289
(52
): 36101-15
PMID25371200
show ga
Ascl2, a basic helix-loop-helix transcription factor, is a downstream target of
WNT signaling that controls the fate of intestinal cryptic stem cells and colon
cancer progenitor cells. However, its involvement in colon cancer and downstream
molecular events is largely undefined; in particular, the mechanism by which
Ascl2 regulates the plasticity of epithelial-mesenchymal transition (EMT) and
mesenchymal-epithelial transition (MET) programs in colon cancer cells remains
unknown. In this study, we systematically demonstrate that Ascl2 loss of function
in colon cancer cells promotes MET by derepressing the expression of microRNA
(miR)-200s (i.e. miR-200b, miR-200a, miR-429, miR-200c, and miR-141) and further
activating their expression through a transcriptional mechanism that involves
direct binding to the most proximal E-box (E-box2) in the miR-200b-a-429
promoter. Activation of miR-200s due to Ascl2 deficiency led to the inhibition of
ZEB1/2 expression and the alteration of epithelial and mesenchymal features.
Transfection of miR-200b, miR-200a, and miR-429 inhibitors into Ascl2-deficient
colon cancer cells promoted the epithelial-mesenchymal transition in a reversible
manner. Transfection of miR-200a or miR-429 inhibitors into Ascl2-deficient colon
cancer cells increased cellular proliferation and migration. Ascl2 mRNA levels
and the miR-200a, miR-200b, miR-200c, miR-141, or miR-429 levels in the colon
cancerous samples were inversely correlated. These results provide the first
evidence of a link between Ascl2 and miR-200s in the regulation of EMT-MET
plasticity in colon cancer.
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