| Summary: | 博士 === 國立陽明大學 === 生化暨分子生物研究所 === 99 === Tumor hypoxia is associated with malignant biological phenotype including enhanced invasiveness, angiogenesis, migration and metastasis. Hypoxia inducible factor-1? (HIF-1?? is a key transcription factor that is induced by hypoxia and is implicated in tumor progression/metastasis. TWIST, a basic helix-loop-helix (bHLH) transcription factor, plays a crucial role in epithelial-mesenchymal transition (EMT), one of the major mechanisms contributing to metastasis. The detail molecular mechanism of HIF-1??npromoted metastasis is poorly understood. Here, we showed that hypoxia/HIF-1??npromoted EMT and increased migration /invasiveness/metastasis both in vitro and in vivo through the direct up-regulation of TWIST expression. Moreover, co-expression of HIF-1? and TWIST/Snail was tightly correlated with metastasis and poor prognosis in cancer patients.
Histone deacetylases (HDACs) are enzymes that regulate gene expression by deacetylating core histone proteins. Recently, HDACs have been shown to implicate in tumorigenesis and metastasis. Here, we demonstrated that the expression of histone deacetylase 3 (HDAC3) was directly induced by HIF-1? in hypoxic condition and HDAC3 was essential for EMT phenotype and metastasis induced by hypoxia. HDAC3 cooperated with Snail and caused deacetylation of acetylated Histone H3 lysine 4 (H3K4Ac), leading to repression of epithelial genes in response to hypoxia. In addition, HDAC3 recruited WDR5, a key component of mixed-lineage leukemia (MLL) complex, and associated with mesenchymal gene promoters to increase H3K4-specific histone methyltransferase (HMT) activity and activate mesenchymal gene expression. Collectively, these results demonstrate that hypoxia/HIF-1 induces EMT through the direct activation of TWIST or HDAC3 expression and show the essential role of HDAC3 and WDR5 in regulation of EMT markers expression under hypoxia. The coordinated networks between the EMT regulators and the epigenetic regulators indicate the complexity of EMT and metastasis regulated by hypoxia and highlight the potential use of epigenetic inhibitors in clinical treatment.
|
|---|
