TWIST activation by hypoxia inducible factor-1 (HIF-1): Implications in metastasis and development

Abstract

Hypoxia is a microenvironmental factor which plays a critical role in development and tumor progression. The hypoxic response is mainly mediated by hypoxia inducible factor-1 (HIF-1) composed of HIF-1alpha and HIF-1beta, which becomes active under low oxygen condition. HIF-1 activates the transcription of hypoxia inducible genes which regulate diverse cellular functions including metabolism, angiogenesis, and invasion. In cancer metastasis, HIF-1-regulated genes promote angiogenesis, invasion, and epithelial-mesenchymal transition (EMT), a critical step of metastasis. TWIST is a master regulator of gastrulation and mesoderm specification and is recently implicated to be essential to mediate cancer metastasis. We recently showed that HIF-1 promotes EMT through direct regulation of TWIST expression. TWIST is critical for hypoxia mediated EMT and metastasis. TWIST plays a non-redundant role in relation to other EMT regulators (e.g. Snail) under hypoxia. Co-expression of HIF-1alpha, TWIST and Snail could be used as a prognostic marker in cancer patients. These findings suggest that hypoxia and/or HIF-1 orchestrates EMT and metastasis through the coordinated regulation of different EMT regulators. Our results provide the important link between hypoxia and developmental processes regulated by TWIST. The implications of the roles of hypoxia and TWIST in early embryonic development are discussed.