Ets1 facilitates EMT/invasion through Drp1-mediated mitochondrial fragmentation in ovarian cancer

Deepshikha Ghosh; Suman Pakhira; Damayanti Das Ghosh; Susanta Roychoudhury; Sib Sankar Roy

doi:10.1016/j.isci.2023.107537

Ets1 facilitates EMT/invasion through Drp1-mediated mitochondrial fragmentation in ovarian cancer

iScience. 2023 Aug 2;26(9):107537. doi: 10.1016/j.isci.2023.107537. eCollection 2023 Sep 15.

Authors

Deepshikha Ghosh¹, Suman Pakhira¹, Damayanti Das Ghosh², Susanta Roychoudhury¹, Sib Sankar Roy^{1

3}

Affiliations

¹ Cell Biology and Physiology Division, CSIR Indian Institute of Chemical Biology (CSIR IICB), 4, Raja S.C. Mullick Road, Kolkata 700032, India.
² Molecular and Diagnostics Laboratory, Basic and Translational Research, Saroj Gupta Cancer Centre & Research Institute, Thakurpukur, Kolkata 700063, India.
³ Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.

Abstract

Ovarian cancer has sustained as a major cause of cancer-related female mortality owing to its aggressive nature and a dearth of early detection markers. Ets1 oncoprotein, a transcription factor belonging to the Ets family, is a well-established promoter of epithelial to mesenchymal transition (EMT) and a prospective malignancy marker in ovarian cancer. Our study establishes Ets1 as a regulator of mitochondrial fission-fusion dynamics through Drp1 augmentation via direct binding at DNM1L (DRP1) promoter. Ets1 overexpression-mediated Drp1 increment resulted in mitochondrial load reduction and compromised OXPHOS Complex 5 (ATP synthase) expression, facilitating a greater reliance on glycolysis over OXPHOS. Furthermore, our work demonstrates that inhibition of mitochondrial fission through molecular or pharmacological inhibition of Drp1 successfully mitigates Ets1-associated EMT in both in vitro and in vivo syngeneic mice model. Collectively, our data highlight the role of Drp1-mediated mitochondrial fragmentation in driving Ets1-mediated bioenergetic alterations and EMT/invasion in ovarian cancer.

Keywords: Cancer; Molecular biology.