1. Department of Thoracic Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
2. Department of Clinical Laboratory, Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Yangzhou University, Kunshan, China.
3. Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China.
4. Department of Thoracic Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, China.
5. Department of Thoracic Surgery, The First Affiliated Hospital of Shaoyang University, Shaoyang, China.
6. Department of Thoracic Surgery, The Central Hospital of Shaoyang, Shaoyang, China.
7. Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China.
8. Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Soochow University, Suzhou, China.
9. Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China.
*These authors contributed equally to this work.
The expression and biological function of the mitochondrial inner membrane protease YME1L (YME1 Like 1 ATPase) in NSCLC are tested here. Bioinformatical analyses and results from local human tissues show that YME1L expression is elevated in NSCLC tissues. YME1L upregulation was observed in primary and immortalized NSCLC cells. In NSCLC cells, shRNA-mediated silence of YME1L or dCas9/sgRNA-induced knockout (KO) of YME1L robustly suppressed cell growth and migration, and provoking apoptosis. YME1L shRNA/KO resulted in mitochondrial dysfunctions in NSCLC cells, leading to mitochondrial depolarization, ROS accumulation and ATP depletion. Conversely, ectopic YME1L overexpression augmented NSCLC cell proliferation and motility. Akt-S6K1 phosphorylation was reduced after YME1L shRNA/KO in primary NSCLC cells, but augmented after YME1L overexpression. Importantly, YME1L KO-caused anti-NSCLC cell activity was attenuated by a constitutively-activate Akt1 (S473D) construct. In vivo, subcutaneous NSCLC xenograft growth was remarkably slowed following intratumoral YME1L shRNA AAV injection in nude mice. YME1L knockdown, Akt-mTOR inactivation and ATP reduction were detected in YME1L-silenced NSCLC xenografts. Taken together, overexpressed YME1L in NSCLC exerts pro-tumorigenic function.