Volume 30 Issue 4 - April 1, 2016 PDF
Counter
Global Oct4 target gene analysis reveals novel downstream PTEN and TNC genes required for drug-resistance and metastasis in lung cancer
Yen-An Tang1,2, Chi-Hsin Chen2, H. Sunny Sun3, Chun-Pei Cheng4, Vincent S. Tseng4,5, Han-Shui Hsu6, Wu-Chou Su7, Wu-Wei Lai8, Yi-Ching Wang1,2*
1Institute of Basic Medical Sciences, National Cheng Kung University, No.1, University Road, Tainan 701, Taiwan; 2Department of Pharmacology, National Cheng Kung University, No.1, University Road, Tainan 701, Taiwan; 3Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan 701, Taiwan; 4Department of Computer Science and Information Engineering, National Cheng Kung University, No.1, University Road, Tainan 701, Taiwan; 5Institute of Medical Informatics, College of Electrical Engineering and Computer Science, National Cheng Kung University, No.1, University Road, Tainan 701, Taiwan; 6Division of Thoracic Surgery, Taipei Veterans General Hospital; Institute of Emergency and Critical Care Medicine, National Yang-Ming University School of Medicine, No.155, Sec.2, Linong Street, Taipei 112, Taiwan; 7Department of Internal Medicine, National Cheng Kung University Hospital, No.138, Sheng Li Road, Tainan 704, Taiwan; 8Department of Surgery, National Cheng Kung University Hospital, No.138, Sheng Li Road, Tainan 704, Taiwan
 
Font Enlarge
Oct4, encoded by POU5F1, is one of the key transcription factors for maintaining pluripotency of embryonic stem cells (ESCs). Although the genome-wide binding profile of Oct4 in ESCs has been reported, little is known about those in somatic cancer cells or tumor-initiating cells (TICs). To explore the underlying mechanism of Oct4 in driving somatic cancer into TIC-like states, we conducted chromatin-immunoprecipitation sequencing (ChIP-seq) to build the genome-wide Oct4 binding profile in A549 lung adenocarcinoma cells. Our results demonstrated that Oct4 occupied at promoter and enhancer regions of genes involved in tumorigenesis pathways, such as cellular movement, cellular growth and proliferation, cell death and survival, and development control. In addition, ChIP-seq analysis revealed novel Oct4-binding motifs in A549 lung adenocarcinoma cells which overlapped with DNA elements for Sp1 transcription factor. Validation of ChIP-seq analysis showed that Oct4 suppressed the expression of tumor suppressor genes, such as PTEN leading to drug resistance, or transactivated oncogenes, such as TNC leading to cancer invasion and metastasis. Our study also dissects the mechanism of Oct4 differential regulation on downstream genes. In the context of PTEN promoter, Sp1 serves as a platform for Oct4 binding and thus Oct4 recruits histone deacetylases HDAC1/2 complex to the PTEN promoter. In contrast, Oct4 transactives TNC expression in a Sp1-independent manner (Figure 1). In clinical study, we found an inverse correlation between Oct4 and PTEN protein expression in lung cancer, while patients with high Oct4 expression showed concordantly increased TNC (Figure 2A). Notably, lung cancer patients with high expression of Oct4 and TNC and low expression of PTEN showed worse progression-free survival compared to patients with normal expression of the corresponding proteins (Figure 2B). Our study provides compelling evidence from lung cells, animal and clinical studies that Oct4-driven transcriptional program promotes drug-resistance and metastasis through PTEN and TNC, respectively.
Figure 1. Working models of differential targeting of Oct4, Sp1 and HDAC1/2 complex at PTEN and TNC promoters. Oct4 cooperates with Sp1 and HDAC1/2 complex to suppress PTEN expression while Oct4 can transactivate TNC expression independent of Sp1.

Figure 2. High Oct4 protein coincides with low PTEN and high TNC levels and poor progression-free survival of lung cancer patients. (A) Representative immunohistochemistry images of Oct4, PTEN and TNC proteins in tumor specimen of lung cancer patients. Oct4 positive immunoreactivity (+), PTEN negative immunoreactivity (–) and TNC positive immunoreactivity (+) were found in patient 1, whereas patient 2 shows a reverse pattern. Original magnification × 200. The insets are a higher magnification of the boxed areas. (B) Progression-free survival analyses indicated that patients with high Oct4 combined with both low PTEN and high TNC expression had significantly poorer survival than other patients. P-values for survival analyses were determined using log-rank test.
< Previous
Next >
Copyright National Cheng Kung University