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SNAI2/Slug gene is silenced in prostate cancer and regulates neuroendocrine
differentiation, metastasis-suppressor and pluripotency gene expression
#MMPMID25686823
Esposito S
; Russo MV
; Airoldi I
; Tupone MG
; Sorrentino C
; Barbarito G
; Di Meo S
; Di Carlo E
Oncotarget
2015[Jul]; 6
(19
): 17121-34
PMID25686823
show ga
Prostate Cancer (PCa)-related deaths are mostly due to metastasization of poorly
differentiated adenocarcinomas often endowed with neuroendocrine differentiation
(NED) areas.The SNAI2/Slug gene is a major regulator of cell migration and tumor
metastasization. We here assessed its biological significance in NED, and
metastatic potential of PCa.SNAI2 expression was down-regulated in most PCa
epithelia, in association with gene promoter methylation, except for cell
clusters forming: a. the expansion/invasion front of high-grade PCa, b. NED
areas, or c. lymph node metastasis.Knockdown of SNAI2 in PC3 cells down-regulated
the expression of neural-tissue-associated adhesion molecules, Neural-Cadherin,
Neural-Cadherin-2, Neuronal-Cell-Adhesion-Molecule, and of the NED marker
Neuron-Specific Enolase, whereas it abolished Chromogranin-A expression. The
metastasis-suppressor genes, Nm23-H1 and KISS1, were up-regulated, while the
pluripotency genes SOX2, NOTCH1, CD44v6, WWTR1/TAZ and YAP1 were dramatically
down-regulated. Over-expression of SNAI2 in DU145 cells substantiated its ability
to regulate metastasis-suppressor, NED and pluripotency genes. In PCa and lymph
node metastasis, expression of SOX2 and NOTCH1 was highly related to that of
SNAI2.In conclusion, I. SNAI2 silencing in PCa may turn-off the expression of NED
markers and pluripotency genes, while turning-on that of specific
metastasis-suppressors, II. SNAI2 expression in selected PCa cells, by regulating
their self-renewal, NED and metastatic potential, endows them with highly
malignant properties. SNAI2 may thus constitute a key target for modern
approaches to PCa progression.
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