MicroRNA miR-210 modulates cellular response to hypoxia through the MYC antagonist MNT.
The hypoxia-inducible factor (HIF) pathway is essential for cell survival under low oxygen and plays an important role in tumor cell homeostasis. We investigated the function of miR-210, the most prominent microRNA upregulated by hypoxia and a direct transcriptional target of HIFs. miR-210 expression was elevated in multiple cancer types and correlated with metastasis of breast and melanoma tumors. miR-210 overexpression in cancer cell lines bypassed hypoxia-induced cell cycle arrest and partially reversed the hypoxic gene expression signature. We identified MNT, a known MYC antagonist, as a miR-210 target. MNT mRNA contains multiple miR-210 binding sites in the 3' UTR and its knockdown phenocopied miR-210 overexpression. Furthermore, loss of MYC abolished miR-210-mediated override of hypoxia-induced cell cycle arrest. Comparison of miR-210 and MYC overexpression with MNT knockdown signatures also indicated that miR-210 triggered a "MYC-like" transcriptional response. Thus, miR-210 influences the hypoxia response in tumor cells through targeting a key transcriptional repressor of the MYC-MAX network.
Zhang
Zhan
Z
Rosetta Inpharmatics LLC, Seattle, WA, USA. microRNA210@yahoo.com
Sun
Hong
H
Dai
Hongyue
H
Walsh
Ryan M
RM
Imakura
Maki
M
Schelter
Janell
J
Burchard
Julja
J
Dai
Xudong
X
Chang
Aaron N
AN
Diaz
Robert L
RL
Marszalek
Joseph R
JR
Bartz
Steven R
SR
Carleton
Michael
M
Cleary
Michele A
MA
Linsley
Peter S
PS
Grandori
Carla
C
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001665:Binding Sites; D002453:Cell Cycle; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D055785:Gene Knockdown Techniques; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D051793:Hypoxia-Inducible Factor 1; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C543800:MIRN210 microRNA, human; C106465:MNT protein, human