1. An epigenetic increase in mitochondrial fission by MiD49 and MiD51 regulates the cell cycle in cancer: Diagnostic and therapeutic implications
- Author
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Elizabeth Lightbody, Bruce E. Elliott, Stephen L. Archer, Edward A. Sykes, Patricia D.A. Lima, Kuang-Hueih Chen, Ashley Martin, Charles C.T. Hindmarch, Yolanda Madarnas, Sandip SenGupta, Leah R. G. Parlow, Jeffrey Mewburn, Christopher J. Nicol, Chandrakant Tayade, Danchen Wu, Victoria Hoskin, and Asish Dasgupta
- Subjects
Male ,0301 basic medicine ,Lung Neoplasms ,Cell cycle checkpoint ,Mice, Nude ,Apoptosis ,Biology ,Mitochondrial Dynamics ,Biochemistry ,Epigenesis, Genetic ,Mitochondrial Proteins ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Mitosis ,Protein kinase B ,Cell Proliferation ,Mice, Inbred BALB C ,Cell growth ,Cell Cycle ,Cancer ,Middle Aged ,Cell cycle ,Peptide Elongation Factors ,Prognosis ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Survival Rate ,030104 developmental biology ,mitochondrial fusion ,Cancer research ,Female ,Mitochondrial fission ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Excessive proliferation and apoptosis-resistance are hallmarks of cancer. Increased dynamin-related protein 1 (Drp1)-mediated mitochondrial fission is one of the mediators of this phenotype. Mitochondrial fission that accompanies the nuclear division is called mitotic fission and occurs when activated Drp1 binds partner proteins on the outer mitochondrial membrane. We examine the role of Drp1-binding partners, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51), as drivers of cell proliferation and apoptosis-resistance in non-small cell lung cancer (NSCLC) and invasive breast carcinoma (IBC). We also evaluate whether inhibiting MiDs can be therapeutically exploited to regress cancer. We show that MiD levels are pathologically elevated in NSCLC and IBC by an epigenetic mechanism (decreased microRNA-34a-3p expression). MiDs silencing causes cell cycle arrest through (a) increased expression of cell cycle inhibitors, p27Kip1 and p21Waf1 , (b) inhibition of Drp1, and (c) inhibition of the Akt-mTOR-p70S6K pathway. Silencing MiDs leads to mitochondrial fusion, cell cycle arrest, increased apoptosis, and tumor regression in a xenotransplant NSCLC model. There are positive correlations between MiD expression and tumor size and grade in breast cancer patients and inverse correlations with survival in NSCLC patients. The microRNA-34a-3p-MiDs axis is important to cancer pathogenesis and constitutes a new therapeutic target.
- Published
- 2020
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