C1orf35 contributes to high anabolic metabolism by simultaneously promoting aerobic glycolysis and oxidative phosphorylation in multiple myeloma cells

Similar to Other malignancies, multiple myeloma (MM) has acquired several functional capabilities known as "Hallmarks of cancer", and one of them is the deregulation of cell metabolism, especially glucose metabolism. Our current study focuses on the role of Chromosome 1 Open Reading Frame 35(C1orf35) in the glucose metabolism of MM cells. We found that the expression of C1orf35 was negative correlated with the overall survival of MM patients, MM cell lines with high C1orf35 expression not only had a faster proliferation rate but also higher levels of both aerobic glycolysis and Oxidative Phosphorylation (OXPHOS). Mechanistic studies revealed that C1orf35 promoted aerobic glycolysis through the c-Myc/PKM2 pathway and interacted with Leucine-Rich PPR Motif-Containing Protein (LRPPRC) to enhance OXPHOS. Moreover, treating MM cells with Gossypol Acetic Acid (GAA), a small molecule inhibitor specifically targeting LRPPRC, unexpectedly led to the degradation of C1orf35 protein and an "energy crisis" in these cells. Finally, we confirmed C1orf35 is on the upstream of PI3K/Akt/mTOR pathway, thus C1orf35 may play a pivotal role in anabolic metabolism. Our study uncovers a "C1orf35-driven" energy metabolism model in MM cells, providing new insights into the pathogenesis of MM and a potential novel target for the treatment of Cancer cells with a high"C1orf35-driven" anabolic metabolism. Schematic diagram of C1orf35 simultaneously promotes glycolysis and OXPHOS.