Lin28 Enhances De Novo Fatty Acid Synthesis To Promote Cancer Progression Via SREBP-1

Metabolic remodeling is one of the important hallmarks in cancer,and metabolic disorder in lipid metabolism is an important part.Fatty acid synthesis is upregμlated in multiply type of cancers,but the mechanism of regulation is not clear.Lin28 is a conserved RNA binding protein,and plays an important role in development,stemness,tumorigenesis and metabolism.Lin28 has two isoforms in human,Lin28A and Lin28B,which have similar functions.Lin28 plays an important role in promoting tumor development,whereas its exact functions and underlying mechanisms are largely unknown.Our previous exploration has found that Lin28A/B regulate Warburg effect via let-7 and PDK1.However,there is not report between Lin28 and lipid metabolism.SREBP-1 is an important transcription factor in fatty acid synthesis to regulate the enzymes of fatty acid synthesis,and is highly expressed in cancer.Since Lin28 and SREBP-1 are important factor in cancer cells,it’s vital to explore whether Lin28 regulates lipid metabolism via SREBP-1 to promote tumorigenesis and progression.Here we show that both human homologs of Lin28 accelerate de novo fatty acid synthesis and promote the conversion from saturated to unsaturated fatty acids via the regulation of SREBP-1.By directly binding to the mRNAs of both SREBP-1 and SCAP,Lin28A/B enhance the translation and maturation of SREBP-1,and protect cancer cells from lipotoxicity.Lin28A/B-stimulated tumor growth is abrogated by SREBP-1 inhibition,and by the impairment of the RNA binding properties of Lin28A/B,respectively.Collectively,our findings uncover that post-transcriptional regulation by Lin28A/B enhances de novo fatty acid synthesis and metabolic conversion of saturated and unsaturated fatty acids via SREBP-1,which is critical for cancer progression.