SNAI2/Slug gene is silenced in prostate cancer and regulates neuroendocrine differentiation, metastasis-suppressor and pluripotency gene expression

Abstract

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.

MicroRNA and Transcription Factor Gene Regulatory Network Analysis Reveals Key Regulatory Elements Associated with Prostate Cancer Progression

“…Also the downregulation of SNAI2 , ITGA3 , BCL2 , PGR , IGFPB3 and HOXD10 was previously reported for prostate cancer [8,36,75–78]. Based on the regulatory network analysis of primary prostate tumor, HOXD10 , BCL2 and PGR are 3 key elements in the network.…”

EMT, stemness and tumor plasticity in aggressive variant neuroendocrine prostate cancers

“…LNCaP C-33 cells, which bear a neuroendocrine phenotype, endogenously express high levels of Snail. Further, inhibition of Snail expression in neuroendocrine-like PC3 cells abolishes NE differentiation attributes and also significantly down-regulates the pluripotency factor Sox2 [68]. Similarly, loss of Slug (a related zinc finger transcription factor) is sufficient to block EMT in PC3 cells [69].…”

The miR‐203/SNAI2 axis regulates prostate tumor growth, migration, angiogenesis and stemness potentially by modulating GSK‐3β/β‐CATENIN signal pathway

“…In vivo xenograft assays have revealed that SNAI2 promotes prostate cancer cell migration and invasion and mediates Cyclin D1‐induced oncogenesis . SNAI2 silencing in PCa suppresses the expression of multiple pluripotency genes, and activates specific metastasis‐suppressors . Ectopic expression of SNAI2 in selected PCa cells promotes their self‐renewal and increases the metastatic potential, endows them with highly malignant properties .…”

“…SNAI2 silencing in PCa suppresses the expression of multiple pluripotency genes, and activates specific metastasis‐suppressors . Ectopic expression of SNAI2 in selected PCa cells promotes their self‐renewal and increases the metastatic potential, endows them with highly malignant properties . SNAI2 may be a critical target for molecular approaches to prevent PCa progression.…”