SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes

被引：43

作者：

Tajima, Ken ^{[1
]}

Yae, Toshifumi ^{[1
]}

Javaid, Sarah ^{[1
]}

Tam, Oliver ^{[2
]}

Comaills, Valentine ^{[1
]}

Morris, Robert ^{[1
]}

Wittner, Ben S. ^{[1
]}

Liu, Mingzhu ^{[1
]}

Engstrom, Amanda ^{[1
]}

Takahashi, Fumiyuki ^{[1
]}

Black, Joshua C. ^{[1
]}

Ramaswamy, Sridhar ^{[1
]}

Shioda, Toshihiro ^{[1
]}

Hammell, Molly ^{[2
]}

Haber, Daniel A. ^{[1
]}

Whetstine, Johnathan R. ^{[1
]}

Maheswaran, Shyamala ^{[1
,3
]}

机构：

[1] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA

[2] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[3] Harvard Univ, Sch Med, Dept Surg, Charlestown, MA 02129 USA

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

关键词：

PROSTATE-CANCER; CLIP-SEQ; EXPRESSION; MICRORNAS; LUNG; TUMORIGENESIS; METHYLATION; STARBASE; BTG2; SITE;

D O I：

10.1038/ncomms9257

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Expression of the p53-inducible antiproliferative gene BTG2 is suppressed in many cancers in the absence of inactivating gene mutations, suggesting alternative mechanisms of silencing. Using a shRNA screen targeting 43 histone lysine methyltransferases (KMTs), we show that SETD1A suppresses BTG2 expression through its induction of several BTG2-targeting miRNAs. This indirect but highly specific mechanism, by which a chromatin regulator that mediates transcriptional activating marks can lead to the downregulation of a critical effector gene, is shared with multiple genes in the p53 pathway. Through such miRNA-dependent effects, SETD1A regulates cell cycle progression in vitro and modulates tumorigenesis in mouse xenograft models. Together, these observations help explain the remarkably specific genetic consequences associated with alterations in generic chromatin modulators in cancer.

引用

页数：9

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