Regulation of IL-20 Expression by Estradiol through KMT2B-Mediated Epigenetic Modification.
Cytokines are low molecular weight regulatory proteins, or glycoproteins, with both tumor-promoting and inhibitory effects on breast cancer growth. Different cytokines play important roles in breast cancer initiation and progression. Here, we show that of the 39 interleukin (IL) genes, IL-20 is the only gene over-expressed in MCF-7 cells treated with estradiol (E2) and that induction of IL-20 expression by estrogen was epigenetically regulated. Methylation of histone H3K4 in the IL-20 promoter was shown to occur via the specific recruitment of KMT2B by estrogen receptor alpha (ERα), but not by other members of the mixed-lineage leukemia (MLL) family of histone methyltransferases. Depletion of KMT2B, or IL-20, disrupts estrogen signaling, attenuates cell proliferation, reduces colony formation, and results in cell cycle arrest. Furthermore, we demonstrated that KMT2B-mediated epigenetic modification also affected the expression of several ERα target genes. IL-20 and KMT2B expression were also associated with ERα-positive breast cancer tissues. We have revealed an important role for KMT2B in the epigenetic transcriptional regulation of cytokine IL-20, and other ERα-responsive genes, in breast cancer cells. Inhibition of IL-20 and KMT2B may have therapeutic benefits in ERα-positive breast cancer.
Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei 11221, Taiwan, Republic of China.
Chia-Hsin
CH
Su
The Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan.
I-Hsuan
IH
Lin
VYM Genome Research Center, National Yang-Ming University, University System of Taiwan, Taipei 11221, Taiwan, Republic of China.
Tsai-Yu
TY
Tzeng
Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei 11221, Taiwan, Republic of China.
Wen-Ting
WT
Hsieh
Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei 11221, Taiwan, Republic of China.|Chien-Tien Hsu Cancer Research Foundation, Taipei 11221, Taiwan, Republic of China.
Ming-Ta
MT
Hsu
D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic; D015854:Up-Regulation
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D006657:Histones; D007378:Interleukins; D004958:Estradiol; D011495:Histone-Lysine N-Methyltransferase; C000619080:KMT2B protein, human; C422042:interleukin 20