The telomerase reverse transcriptase (hTERT) gene is a direct target of the histone methyltransferase SMYD3.
Recent evidence has accumulated that the dynamic histone methylation mediated by histone methyltransferases and demethylases plays key roles in regulation of chromatin structure and transcription. In the present study, we show that SET and MYND domain-containing protein 3 (SMYD3), a histone methyltransferase implicated in oncogenesis, directly trans-activates the telomerase reverse transcriptase (hTERT) gene that is essential for cellular immortalization and transformation. SMYD3 occupies its binding motifs on the hTERT promoter and is required for maintenance of histone H3-K4 trimethylation, thereby contributing to inducible and constitutive hTERT expression in normal and malignant human cells. Knocking down SMYD3 in tumor cells abolished trimethylation of H3-K4, attenuated the occupancy by the trans-activators c-MYC and Sp1, and led to diminished histone H3 acetylation in the hTERT promoter region, which was coupled with down-regulation of hTERT mRNA and telomerase activity. These results suggest that SMYD3-mediated trimethylation of H3-K4 functions as a licensing element for subsequent transcription factor binding to the hTERT promoter. The present findings provide significant insights into regulatory mechanisms of hTERT/telomerase expression; moreover, identification of the hTERT gene as a direct target of SMYD3 contributes to a better understanding of SMYD3-mediated cellular transformation.
Liu
Cheng
C
Department of Medicine, Division of Hematology, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
Fang
Xiaolei
X
Ge
Zheng
Z
Jalink
Marit
M
Kyo
Satoru
S
Björkholm
Magnus
M
Gruber
Astrid
A
Sjöberg
Jan
J
Xu
Dawei
D
D000107:Acetylation; D001483:Base Sequence; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism
D006657:Histones; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D011495:Histone-Lysine N-Methyltransferase; C506278:SMYD3 protein, human; D019098:Telomerase