Metallothionein 1 h tumour suppressor activity in prostate cancer is mediated by euchromatin methyltransferase 1.
Metallothioneins (MTs) are a group of metal binding proteins thought to play a role in the detoxification of heavy metals. Here we showed by microarray and validation analyses that MT1h, a member of MT, is down-regulated in many human malignancies. Low expression of MT1h was associated with poor clinical outcomes in both prostate and liver cancer. We found that the promoter region of MT1h was hypermethylated in cancer and that demethylation of the MT1h promoter reversed the suppression of MT1h expression. Forced expression of MT1h induced cell growth arrest, suppressed colony formation, retarded migration, and reduced invasion. SCID mice with tumour xenografts with inducible MT1h expression had lower tumour volumes as well as fewer metastases and deaths than uninduced controls. MT1h was found to interact with euchromatin histone methyltransferase 1 (EHMT1) and enhanced its methyltransferase activity on histone 3. Knocking down of EHMT1 or a mutation in MT1h that abrogates its interaction with EHMT1 abrogated MT1h tumour suppressor activity. This demonstrates tumour suppressor activity in a heavy metal binding protein that is dependent on activation of histone methylation.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Yu-Chen
YC
Han
Zhong-Liang
ZL
Zheng
Ze-Hua
ZH
Zuo
Yan P
YP
Yu
Rui
R
Chen
George C
GC
Tseng
Joel B
JB
Nelson
Jian-Hua
JH
Luo
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D046228:Microarray Analysis; D010414:Pennsylvania / Q000453:epidemiology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D025521:Tumor Suppressor Proteins; C582205:metallothionein 1 h, human; D008668:Metallothionein; C455847:EHMT1 protein, human; D011495:Histone-Lysine N-Methyltransferase