The interleukin 6 family of cytokines including leukemia inhibitory factor (LIF) regulates the progression of several types of cancer. However, although LIF overexpression during breast cancer progression was observed in our previous report, the molecular mechanisms responsible for this deregulation remain largely unknown. Here we show that LIF expression is epigenetically up-regulated via DNA demethylation and changes in histone methylation status within its promoter region in the isogenic MCF10 model. Bisulfite sequencing revealed the CpG pairs within the promoter region are hypermethylated in normal breast epithelial cells, but extensively demethylated as breast cancer progresses. In agreement with the DNA methylation pattern, our chromatin immunoprecipitation showed that inactive epigenetic marks such as MeCP2 occupancy and histone H3-Lys9-dimethylation significantly decreased during the progression to breast cancer but an active histone mark was increased in an inverse manner. Also, the occupancy of the transcription factor Sp1, which has higher affinity for hypomethylated CpGs, increased. RNAimediated knockdown of LIF expression resulted in a significant reduction of cell growth and colony formation in breast cancer cells, suggesting the potential role of LIF-LIF receptor axis in autocrine stimulation of cancer cells. Collectively, our data suggest that the epigenetic up-regulation of the LIF gene likely play an important role in the development of breast cancer.
Bibliographical noteFunding Information:
We thank Fred Miller and S.J. Santner for providing human breast cell lines kindly. This work was supported by National Research Foundation of Korea Grant funded by the Korean Government Ministry of Education, Science and Technology (KRF-2007-313-C00525) and also by Mid-career Researcher Program through National R esearch Foundation of Korea grant funded by the Ministry of Education, Science and Technology (No. R01-2007-000-20047-0 (2007) or 2009-0083772). In addition, this study was in part supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea (No. 0920260) to Y.K.J.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology