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An epigenetic increase in mitochondrial fission by MiD49 and MiD51 regulates the cell cycle in cancer: Diagnostic and therapeutic implications
Author(s) -
Dasgupta Asish,
Chen KuangHueih,
Wu Danchen,
Hoskin Victoria,
Mewburn Jeffrey,
Lima Patricia D. A.,
Parlow Leah R. G.,
Hindmarch Charles C. T.,
Martin Ashley,
Sykes Edward A.,
Tayade Chandrakant,
Lightbody Elizabeth D.,
Madarnas Yolanda,
SenGupta Sandip K.,
Elliott Bruce E.,
Nicol Christopher J. B.,
Archer Stephen L.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201903117r
Subject(s) - epigenetics , cancer , mitochondrial fission , biology , cell cycle , fission , mitochondrion , cancer research , microbiology and biotechnology , computational biology , genetics , physics , gene , quantum mechanics , neutron
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, p27 Kip1 and p21 Waf1 , (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.