Clinical and in vitro study demonstrating that MOTS-c levels are reduced in serum and tumor tissue of ovarian cancer patients, correlating with poor prognosis, and that exogenous MOTS-c suppresses OC cell proliferation, migration, and invasion by attenuating USP7-mediated deubiquitination of LARS1 (leucyl-tRNA synthetase 1). Identifies a novel OC tumor suppressor mechanism. Establishes MOTS-c as a tumor suppressor in ovarian cancer with a specific molecular mechanism—the USP7-LARS1 deubiquitination axis—providing both a potential biomarker for OC prognosis and a novel therapeutic target for one of the most lethal gynecologic malignancies.
Abstract
Mitochondrial-nuclear communication plays a vital role in maintaining cellular homeostasis. MOTS-c, a short peptide derived from the 12S rRNA of mitochondrial DNA, has been suggested as a retrograde mitochondrial signal. Although recent clinical studies have suggested a possible link between MOTS-c and human cancer, the role of MOTS-c in tumorigenesis has yet to be investigated. Here, MOTS-c levels are found to be reduced in both serum and tumor tissues from ovarian cancer (OC) patients, which are associated with poor patients' prognosis. Exogenous MOTS-c inhibits the proliferation, migration and invasion of OC cells, and induces cell cycle arrest and apoptosis. Mechanistically, MOTS-c interacts with LARS1 and promotes its ubiquitination and proteasomal degradation. In addition, USP7 was identified as a deubiquitinase of LARS1, and MOTS-c can attenuates USP7-mediated LARS1 deubiquitination by competing with USP7 for binding to LARS1. Besides, LARS1 was found to be increased and play an important oncogenic function in OC. More importantly, MOTS-c displays a marked anti-tumor effect on OC growth without systemic toxicity in vivo. In conclusion, this study reveals a crucial role of MOTS-c in OC and provides a possibility for MOTS-c as a therapeutic target for the treatment of this manlignacy.