Epigenetic reprogramming and post-transcriptional regulation during the epithelial-mesenchymal transition.

The epithelial-mesenchymal transition (EMT) is a developmental process that is important for organ development, metastasis, cancer stemness, and organ fibrosis. The EMT process is regulated by different signaling pathways as well as by various epigenetic and post-transcriptional mechanisms. Here, we review recent progress describing the role of different chromatin modifiers in various signaling events leading to EMT, including hypoxia, transforming growth factor (TGF)-ß, Notch, and Wnt. We also discuss post-transcriptional mechanisms, such as RNA alternative splicing and the effects of miRNAs in EMT regulation. Furthermore, we highlight on-going and future work aimed at a detailed understanding of the epigenetic and post-transcriptional mechanisms that regulate EMT. This work will shed new light on the cellular and tumorigenic processes affected by EMT misregulation.

Linkage between Twist1 and Bmi1: molecular mechanism of cancer metastasis/stemness and clinical implications.

Cancer metastasis is the major cause of cancer-related death despite significant improvements in multimodal cancer therapy. Epithelial-mesenchymal transition (EMT), a major mechanism of cancer metastasis, is a process that generates cells with stem cell-like properties (cancer stemness). Cancer stemness is a concept that describes a minor population of cells (cancer stem cells) residing within a tumour that are able to self-renew and are resistant to conventional therapy. The mechanisms delineating the generation of cancer stemness and its connection to cancer metastasis remain largely unknown. Twist1 is an EMT regulator and increased Twist1 expression, which has prognostic significance in various human cancers, has been widely reported. Bmi1 is a critical component of polycomb repressive complex (PRC) 1, which maintains self-renewal and stemness. Bmi1 is frequently overexpressed in different types of human cancers and can induce drug resistance (Table 2). Recent studies have shown that Twist1 directly activates Bmi1 expression and that these two molecules function together to mediate cancer stemness and EMT. These results present a unique mechanism of EMT-induced cancer metastasis and stemness. Further investigation of the mechanisms of EMT-mediated cancer metastasis and stemness will contribute to the management and treatment of metastatic cancers.

Induction of HSPA4 and HSPA14 by NBS1 overexpression contributes to NBS1-induced in vitro metastatic and transformation activity.

BACKGROUND: Nijmegen breakage syndrome (NBS) is a chromosomal-instability syndrome associated with cancer predisposition, radiosensitivity, microcephaly, and growth retardation. The NBS gene product, NBS1 (p95) or nibrin, is a part of the MRN complex, a central player associated with double-strand break (DSB) repair. We previously demonstrated that NBS1 overexpression contributes to transformation through the activation of PI 3-kinase/Akt. NBS1 overexpression also induces epithelial-mesenchymal transition through the Snail/MMP2 pathway. METHODS: RT-PCR, Western blot analysis, in vitro migration/invasion, soft agar colony formation, and gelatin zymography assays were performed. RESULTS: Here we show that heat shock protein family members, A4 and A14, were induced by NBS1 overexpression. siRNA mediated knockdown of HSPA4 or HSPA14 decreased the in vitro migration, invasion, and transformation activity in H1299 cells overexpressing NBS1. However, HSPA4 or HSPA14 induced activity was not mediated through MMP2. NBS1 overexpression induced the expression of heat shock transcription factor 4b (HSF4b), which correlated with the expression of HSPA4 and HSPA14. CONCLUSION: These results identify a novel pathway (NBS1-HSF4b-HSPA4/HSPA14 axis) to induce migration, invasion, and transformation, suggesting the activation of multiple signaling events induced by NBS1 overexpression.