The Roles of Histone Deacetylase 2 in Tumorigenesis of Oral Cancer
Date Issued
2009
Date
2009
Author(s)
Hsieh, Tsung-Han
Abstract
Oral squamous-cell carcinoma (OSCC) is one of the 10 most frequent cancers worldwide with more than half a million patients being diagnosed each year. Based on our previous study, over 70 % OSCC patients with HDAC2 over-expression were founded. Therefore, the roles of HDAC2 in tumorigenesis were elucidated in this study. We first screened six oral cancer cell lines and found that SAS cells with high expression of HDAC2 but HSC3 cells with low expression. Accordingly, HDAC2 knockdown stable line in SAS and HDAC over-expression stable line in HSC3 were established. SAS cells with HDAC2 knockdown showed slow growth rate, weak colony forming ability, and low metastatic potential in vitro. In contrast, HSC3 cells with HDAC2 over-expression presented fast growth rate, strong colony forming ability, and high metastatic potential in vitro. To illuminate the molecular mechanisms of HDAC2, we performed the whole human genome microarray which displayed that abundant hypoxia-associated genes were regulated by HDAC2. An important molecular regulation was revealed: HDAC2 stabilized HIF-1α protein through deacetylaton of the acetyl group on lysine 532 residue at normoxia and then the deacetylated HIF-1α protein would evade the VHL-ubiquitin-mediated degradation pathway. Considerable HIF-1α proteins accumulated in cytoplasm and also translocated into nucleus for transcriptional activation of hypoxia-induced genes, including MMPs, Collagenases, CCLs, and ANGPTL4. These pro-metastatic proteins facilitated cell survival, migration, invasion, intrvasation, and extravasation have been studied. We further investigated that ANGPTL4 protein involved in tumor migration and invasion in vitro and also confirm that the transcriptional activation of ANGPTL4 was regulated through HDAC2-HIF-1α-mediated pathway. In orthptopic (buccal mucosa injection) animal model, SAS cells with HDAC2 knockdown were low tumorigenesis and weak lymph node metastasis compared with vector controls in vivo, whereas HSC3 cells with HDAC2 over-expression were strong ability for tumorigenesis, growth and high lymph node metastasis compared with controls. Finally, we elucidated the multiple roles of HDAC2 in tumorigenesis and metastatic progression. Targeting of HDAC2 and HIF-1α are a novel strategy for oral cancer therapy.
Subjects
oral cancer
metastasis
HDAC2
HIF-1α
ANGPTL4
SDGs
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