Aberrantly hypermethylated Homeobox A2 derepresses metalloproteinase-9 through TBP and promotes invasion in Nasopharyngeal carcinoma
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Hsin-Pai Li1,2,3,*, Chen-Ching Peng1,*, I-Che Chung2, Mei-Yuan Huang2, Shao-Tung Huang1, Chia-Chun Chen2, Kai-Ping Chang4, Cheng-Lung Hsu5, Yu-Sun Chang1,2
1 Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (ROC)
2 Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan, Republic of China (ROC)
3 Department of Microbiology and Immunology Medical School, Chang Gung University, Taoyuan, Taiwan, Republic of China (ROC)
4 Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Lin-Kou, Taiwan, ROC
5 Division of Hematology-Oncology, Chang Gung Memorial Hospital, Lin-Kou, Taiwan, ROC
* These authors contributed equally to this work.
Hsin-Pai Li , email:
Keywords: HOXA2, DNA methylation, NPC, MMP9
Received: September 4, 2013 Accepted: November 2, 2013 Published: November 4, 2013
Nasopharyngeal carcinoma (NPC) is notorious for its high invasiveness and metastatic ability. In this study, we identified a differential hypermethylated transcription repressor, Homeobox A2 (HOXA2), which may render NPC cells invasive and metastatic. Aberrant hypermethylation of HOXA2 led to low RNA expression in NPC tumors and cells. Addition of methylation inhibitor 5’Aza restored HOXA2 RNA expression in NPC cells. Methylated HOXA2 promoter reduces the binding affinity of the transcriptional co-activator p300, causing transcriptionalrepression of HOXA2. In NPC cells, re-expression of ectopic HOXA2 wascorrelated with decreased invasive ability and reduced metalloproteinase MMP-9 RNA and protein expression. Promoter, ChIP and DNA-pull down assays indicated that HOXA2 competes with the transcription activator, TATA-box binding protein (TBP) for a recognition sequence near the MMP-9 transcription start site, and suppresses MMP-9 transcription. Thus, HOXA2 acts as a suppressor or TBP-antagonist to inhibit MMP-9 expression; while methylation-mediated inactivation of HOXA2 in NPC derepresses MMP-9 production and increases invasion of NPC cells. In NPC plasma samples, increased plasma EBV copy number was correlated with increased in cell-free HOXA2 hypermethylation and elevated MMP-9 levels. Plasma EBV DNA and methylated cell-free HOXA2 can be used as biomarkers for monitoring NPC treatment.
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