Downregulation of nc886 contributes to prostate cancer cell invasion and TGFß1-induced EMT.

Epithelial-to-mesenchymal transition (EMT) activation is important in cancer progression and metastasis. Evidence indicates that nc886 is a representative Pol III gene that processes microRNA products via Dicer and further downregulates its target gene transforming growth factor- ß1 (TGF-ß1), which is the most prominent inducer of EMT in prostate cancer (PC). Consistent with the previous literature, we found that nc886 downregulation was strongly associated with metastatic behavior and showed worse outcomes in PC patients. However, little is known about the association between nc886 and the EMT signaling pathway. We developed a PC cell model with stable overexpression of nc886 and found that nc886 changed cellular morphology and drove MET. The underlying mechanism may be related to its promotion of SNAIL protein degradation via ubiquitination, but not to its neighboring genes, TGFß-induced protein (TGFBI) and SMAD5, which are Pol II-transcribed. TGF-ß1 also override nc886 promotion of MET via transient suppression the transcription of nc886, promotion of TGFBI or increase in SMAD5 phosphorylation. Both nc886 inhibition and TGFBI activation occur regardless of their methylation status. The literature suggests that MYC inhibition by TGF-ß1 is attributed to nc886 downregulation. We incidentally identified MYC-associated zinc finger protein (MAZ) as a suppressive transcription factor of TGFBI, which is controlled by TGF-ß1. We elucidate a new mechanism of TGF-ß1 differential control of Pol II and the transcription of its neighboring Pol III gene and identify a new EMT unit consisting of nc886 and its neighboring genes.

Lamin A/C might be involved in the EMT signalling pathway.

We have previously reported a heterogeneous expression pattern of the nuclear membrane protein lamin A/C in low- and high-Gleason score (GS) prostate cancer (PC) tissues, and we have now found that this change is not associated with LMNA mutations. This expression pattern appears to be similar to the process of epithelial to mesenchymal transition (EMT) or to that of mesenchymal to epithelial transition (MET). The role of lamin A/C in EMT or MET in PC remains unclear. Therefore, we first investigated the expression levels of and the associations between lamin A/C and several common EMT markers, such as E-cadherin, N-cadherin, ß-catenin, snail, slug and vimentin in PC tissues with different GS values and in different cell lines with varying invasion abilities. Our results suggest that lamin A/C might constitute a type of epithelial marker that better signifies EMT and MET in PC tissue, since a decrease in lamin A/C expression in GS 4 + 5 cases is likely associated with the EMT process, while the re-expression of lamin A/C in GS 5 + 4 cases is likely linked with MET. The detailed GS better exhibited the changes in lamin A/C and the EMT markers examined. Lamin A/C overexpression or knockdown had an impact on EMT biomarkers in a cell model by direct regulation of ß-catenin. Hence, we suggest that lamin A/C might serve as a reliable epithelial biomarker for the distinction of PC cell differentiation and might also be a fundamental factor in the occurrence of EMT or MET in PC.