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J Biol Chem. 2017 Dec 15;292(50):20694-20706. doi: 10.1074/jbc.M117.797001. Epub 2017 Oct 24.

Epigenetic modification of miR-663 controls mitochondria-to-nucleus retrograde signaling and tumor progression.

Carden T1, Singh B1, Mooga V1, Bajpai P1, Singh KK2,3,4,5,6,7,8.

Author information

1
From the Departments of Genetics.
2
From the Departments of Genetics, kksingh@uab.edu.
3
Pathology, and.
4
Environmental Health Sciences.
5
Center for Free Radical Biology.
6
Center for Aging, and.
7
UAB Comprehensive Cancer Center, University of Alabama at Birmingham and.
8
Birmingham Veterans Affairs Medical Center, Birmingham, Alabama 35294.

Abstract

The normal cellular function requires communication between mitochondria and the nucleus, termed mitochondria-to-nucleus retrograde signaling. Disruption of this mechanism has been implicated in the development of cancers. Many proteins are known modulators of retrograde signaling, but whether microRNAs (miRNAs) are also involved is unknown. We conducted an miRNA microarray analysis using RNA from a parental cell line, a Rho0 line lacking mitochondrial DNA (mtDNA) and a Rho0 line with restored mtDNA. We found that miR-663 was down-regulated in the mtDNA-depleted Rho0 line. mtDNA restoration reversed this miRNA to parental level, suggesting that miR-663 may be epigenetically regulated by retrograde signaling. By using methylation-specific PCR and bisulfite sequencing we demonstrate that miR-663 promoter is epigenetically regulated not only by genetic but also by pharmacological disruption of oxidative phosphorylation (OXPHOS). Restoration of OXPHOS Complex I inhibitor-induced miR-663 expression by N-acetylcysteine suggested that reactive oxygen species (ROS) play a key role in epigenetic regulation of miR-663. We determined that miR-663 regulates the expression of nuclear-encoded respiratory chain subunits involved in Complexes I, II, III, and IV. miR-663 also controlled the expression of the Complexes I (NDUFAF1), II (SDHAF2), III (UQCC2), and IV (SCO1) assembly factors and was required for stability of respiratory supercomplexes. Furthermore, using luciferase assays, we found that miR-663 directly regulates UQCC2. The anti-miR-663 reduced OXPHOS complex activity and increased in vitro cellular proliferation and promoted tumor development in vivo in mice. We also found that increased miR-663 expression in breast tumors consistently correlates with increased patient survival. We provide the first evidence for miRNA controlling retrograde signaling, demonstrating its epigenetic regulation and its role in breast tumorigenesis.

KEYWORDS:

DNA methylation; OXPHOS; breast cancer; gene expression; miR-663; microRNA (miRNA); mitochondria; retrograde signaling; tumorigenesis

PMID:
29066618
PMCID:
PMC5733605
DOI:
10.1074/jbc.M117.797001
[Indexed for MEDLINE]
Free PMC Article

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