MicroRNA miR-210 modulates cellular response to hypoxia through the MYC antagonist MNT

Abstract

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.

miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity

“…Eight transcripts of this list have already been identified in others cell types using other experimental approaches. 12,15 Moreover, additional miR-210 predicted targets described elsewhere, 12,15,29 including the recently validated gene ISCU, 18 were also identified after relaxing the log 2 ratio cutoff to À0.5, comforting our methodological approach. It remains that the list of proposed miRNA targets always requires a direct validation by western blot analyses and/or reporter plasmid assays.…”

“…[10][11][12] Contradictory data however exist concerning the regulation and roles of miR-210 during cancer progression. miR-210 appears to be overexpressed in most solid tumors 10,[12][13][14][15] but absent in ovarian carcinoma. 11 Furthermore, it has been shown that depending on the tissue type or cellular model, miR-210 was able to either promote entry into the cell cycle 15 and to inhibit apoptosis 16,17 or rather to repress tumor initiation.…”

“…11 Furthermore, it has been shown that depending on the tissue type or cellular model, miR-210 was able to either promote entry into the cell cycle 15 and to inhibit apoptosis 16,17 or rather to repress tumor initiation. 12 Several miR-210 targets have been investigated more specifically in the context of cancer, including cell-cycle regulator E2F3, 11 homeobox proteins (HOXA1, HOXA9), 12 the myc antagnonist MNT 15 and the Iron Sulfur Cluster Assembly Proteins ISCU1/2, 18 which are involved in many cellular processes such as heme biosynthesis and iron metabolism.…”

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

“…These include miR-210 that not only indirectly facilitates HIF activity by targeting GPD1-L but also silences MNT, a member of the MYC/MAD/MYX transcription factor family, which antagonizes the trans-activating function of MYC [42]. This enables MYC-mediated induction of genes involved in the resolution of HIF-induced cell cycle arrest as well as cellular metabolism.…”

A critical role for Mnt in Myc-driven T-cell proliferation and oncogenesis

“…Mnt-Max complexes can compete with Myc-Max for binding to Ebox sites, and deletion or knockdown of Mnt leads to misregulation of a number of wellestablished Myc target genes (15)(16)(17)(18)(19). Moreover, results from combined chromatin immunoprecipitation and transcriptome analysis in breast epithelial cells (20) and transcriptome analysis in Mnt-deficient Drosophila (21,22) and human cells (19) suggest that Mnt and Myc bind and coregulate an overlapping set of target genes. Consistent with the notion that Mnt and Myc are functional antagonists, Mnt deletion or siRNA knockdown was shown to rescue, at least transiently, the proliferative arrest of cells caused by loss of Myc (16,17), and deletion of Drosophila Mnt partially rescued the viability and cell growth defects caused by deletion of Drosophila Myc (21).…”