Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all lung cancer cases. In recent years, therapeutic strategies such as targeted therapy and immunotherapy have been developed. Nevertheless, the 5-year overall survival rate remains low, estimated to range from 21% to 31%. Therefore, there is an urgent need to develop novel therapeutic approaches.
Recently, the research team led by Yao Zhi and Liu Ran from Tianjin Medical University published a research paper titled C19orf12 inhibits mitochondrial function and enhances the antitumor effects of metformin in non-small cell lung cancer in Cell Reports, a sub-journal of Cell.
The study revealed that C19orf12, a gene associated with neurodegenerative diseases, is highly expressed in non-small cell lung cancer (NSCLC) and correlates with poor prognosis. Elevated C19orf12 levels suppress mitochondrial function and potentiate the antitumor effects of metformin in NSCLC.
Metabolic reprogramming facilitates tumor progression and metastasis, offering a potential exploitable avenue for cancer treatment. Tumor cells take up glucose and produce excessive lactate even under adequate oxygen supply, a phenomenon known as aerobic glycolysis, or the Warburg effect, which is widely recognized as a hallmark of cancer. However, metabolic reprogramming in tumors is not limited to the Warburg effect. Cancer cells must balance their energy demands with equally vital requirements for macromolecular biosynthesis and the maintenance of redox homeostasis. Emerging evidence indicates that mitochondrial metabolism plays a critical role in meeting these demands, making it an attractive target for cancer therapy.
C19orf12 is located on human chromosome 19 and encodes a transmembrane protein. Mutations in this gene occur in mitochondrial membrane protein-associated neurodegeneration (MPAN). In MPAN, C19orf12 mutations lead to mitochondrial defects, iron overload, lipid peroxidation and ferroptosis. In addition, C19orf12 amplification has been identified in human breast and ovarian cancers. Nevertheless, its impacts on cancer remain poorly understood, and there have been no reports on C19orf12-mediated tumorigenesis to date. Hence, the full spectrum of functions of C19orf12 remains to be elucidated.
In this new study, the team found that the neurodegeneration-related gene C19orf12 is upregulated in NSCLC, and increased C19orf12 expression is associated with poor prognosis and enhanced metastatic potential in NSCLC.
High levels of C19orf12 inhibit mitochondrial respiration and reduce glucose flux through the tricarboxylic acid (TCA) cycle. Mechanistically, C19orf12 interacts with LRPPRC and suppresses its biological functions, thereby downregulating the expression of genes involved in the mitochondrial electron transport chain (ETC).
The study also demonstrated that C19orf12 synergistically inhibits mitochondrial respiration and sensitizes NSCLC cells to the antitumor effects of metformin.
Key findings of the study:
C19orf12 is highly expressed in NSCLC and correlates with unfavorable prognosis;
C19orf12 regulates mitochondrial function and drives glucose metabolic reprogramming;
C19orf12 downregulates the expression of mitochondrial electron transport chain Complex I and Complex IV via LRPPRC;
C19orf12 sensitizes NSCLC cells to the antitumor activity of metformin.
Collectively, this study highlights the role of C19orf12 as a regulator of mitochondrial metabolism in NSCLC, and suggests that elevated C19orf12 expression may serve as a biomarker to predict improved therapeutic response to metformin.
