Direct regulation of TWIST by HIF-1α promotes metastasis

Abstract

Stabilization of the hypoxia-inducible factor-1alpha (HIF-1alpha) transcription complex, caused by intratumoural hypoxia, promotes tumour progression and metastasis, leading to treatment failure and mortality in different types of human cancers. The transcription factor TWIST is a master regulator of gastrulation and mesoderm-specification and was implicated recently as an essential mediator of cancer metastasis. Notably, HIF-1alpha- and TWIST-null mice show similarities in their phenotypes. Here, we have shown that hypoxia or overexpression of HIF-1alpha promotes epithelial-mesenchymal transition (EMT) and metastastic phenotypes. We also found that HIF-1 regulates the expression of TWIST by binding directly to the hypoxia-response element (HRE) in the TWIST proximal promoter. However, siRNA-mediated repression of TWIST in HIF-1alpha-overexpressing or hypoxic cells reversed EMT and metastastic phenotypes. Co-expression of HIF-1alpha, TWIST and Snail in primary tumours of patients with head and neck cancers correlated with metastasis and the worst prognosis. These results provide evidence of a key signalling pathway involving HIF-1alpha and TWIST that promotes metastasis in response to intratumoural hypoxia.

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…In VHL-deficient renal cell carcinoma, stable expression of the HIF-1α and HIF-2α isoforms is associated with increased expression of Snail, Zeb1 and Zeb2, loss of E-cadherin and an increase in invasion [69,70]. Twist, a master regulator of gastrulation and mesoderm specification, is also essential in mediating cancer metastasis and can be directly regulated by both HIF-1α and HIF-2α [71,72]. In NSCLC and breast cancer cell lines, hypoxia or overexpression of HIF-1α reduced E-cadherin expression and increased cell migration, invasion and metastasis, effects that were reversed by knockdown of Twist by siRNA [71].…”

“…Twist, a master regulator of gastrulation and mesoderm specification, is also essential in mediating cancer metastasis and can be directly regulated by both HIF-1α and HIF-2α [71,72]. In NSCLC and breast cancer cell lines, hypoxia or overexpression of HIF-1α reduced E-cadherin expression and increased cell migration, invasion and metastasis, effects that were reversed by knockdown of Twist by siRNA [71]. Moreover, co-expression of HIF-1α, Twist and Snail in primary tumors of head and neck squamous cell carcinoma (HNSCC) patients correlated with the highest probability of metastasis and the worst prognosis.…”

Transcriptome profiling reveals novel gene expression signatures and regulating transcription factors of TGFβ‐induced epithelial‐to‐mesenchymal transition

“…Indeed, mounting evidence suggests that co‐opting of EMT, an evolutionarily conserved process required for tissue morphogenesis during embryonic development, plays a critical role in tumor invasion, acquisition of cancer stem cell‐like properties, and the development of metastasis and drug resistance 4. While loss of E‐cadherin expression represents a primal event in EMT, we increasingly appreciate that EMT is a complex process that is orchestrated by activation and repression of a growing and still incomplete list of genes, proteins, and transcriptional factors including ZEB1, SNAIL, TWIST, CDH2, and VIM among others 5, 6, 7. Although several different EMT‐related gene expression signatures (GES) have been reported to date attempting to capture key EMT‐associated genes and regulators of EMT, they have been limited in part by variations observed between cell lines, limited concordance between different EMT induction models, and lack of functional validation 8, 9, 10, 11, 12.…”

PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage

“…Twist-1 expression can be regulated by hypoxia-induced HIF-1 through direct binding to the hypoxia-response element in the TWIST proximal promoter. This signaling pathway is thought to promote metastasis in response to intratumoral hypoxia (Yang et al, 2008).…”