Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Abstract

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit.

TGF-β and microRNA Interplay in Genitourinary Cancers

“…These inhibitory NF-κβ effects could not be reversed by the incubation of cells with TGF-β, suggesting that these factors may synergistically induce invasion and EMT in prostate cancer cells [253]. TGF-β-mediated EMT can also be inhibited by Elf5 (through suppression of SMAD3 phosphorylation [254] or FoxA1 [255], and induced by SOX5 [105], CML, CRM1 [256], TRPM7 [257], or SENP1. Interestingly, the latter effect involves SENP1-induced deSUMOylation of SMAD4, leading to its inhibition and induction of EMT [258].…”

Epithelial–mesenchymal transition (EMT): A biological process in the development, stem cell differentiation, and tumorigenesis

“…Loss of E‐cadherin expression is considered a key event in an EMT where the cell–cell contacting modulators, cell polarity‐related cytoskeleton, and extracellular matrix are involved (Puisieux, Brabletz, & Caramel, ). Since first described in 1982 (Greenburg & Hay, ), the EMT has been documented to be regulated by various transcription factors (TFs) (Galvan et al, ; Wei et al, ; Yu et al, ), small non‐coding RNA (Dang, Esparza, Maine, Westcott, & Pearson, ; Zhou et al, ), epigenetic modulators (Choi, Park, et al, ; Cicchini et al, ), and exogenous inducers (An et al, ; Buczek et al, ; Choi, Hong, et al, ; Hwang‐Verslues et al, ; Park et al, ; Zavadil et al, ). Families of the zinc‐finger proteins Snails (Snai1, Snai2/Slug, Snai3/Smuc), the E‐box‐binding proteins Zebs (Zeb1/Tcf8, Zeb2/Sip1), the bHLH protein Twists (Twist1, Twist2), and the forkhead box proteins FOXCs (FOXC1, FOXC2) are major TFs that repress the expression of E‐cadherin directly (Puisieux et al, ).…”

Differential role of PTEN in transforming growth factor β (TGF‐β) effects on proliferation and migration in prostate cancer cells

“…Previous studies have shown that TGF‐β1 and TGF‐β3 exert differential effects on migration and invasion in prostate cancer cells . It has been indicated that TGF‐β3 exerts more potent effects on migratory and invasive behavior.…”