A novel miR-1291-ERR α-CPT1C axis modulates tumor cell proliferation, metabolism and tumorigenesis

Rationale: MicroRNAs are known to influence the development of a variety of cancers. Previous studies revealed that miR-1291 has antiproliferative functions in cancer cells. Carnitine palmitoyltransferase 1C (CPT1C) has a vital role in mitochondrial energy metabolism and modulation of cancer cell proliferation. Since both miR-1291 and CPT1C regulate tumor cell metabolism and cancer progression, we hypothesized that they might be regulated synergistically. Methods: A series of cell phenotype indicators, such as BrdU, colony formation, cell cycle, ATP production, ROS accumulation and cell ability to resist metabolic stress, were performed to clarify the effects of miR-1291 and ERR alpha expression on tumor cell proliferation and metabolism. A xenograft tumor model was used to evaluate cell tumorigenesis. Meta-analysis and bioinformatic prediction were applied in the search for the bridge-link between miR-1291 and CPT1C. RT-qPCR, western-blot and IHC analysis were used for the detection of mRNA and protein expression. Luciferase assays and ChIP assays were conducted for in-depth mechanism studies. Results: The expression of miR-1291 inhibited growth and tumorigenesis as a result of modulation of metabolism. CPT1C expression was indirectly and negatively correlated with miR-1291 levels. ESRRA was identified as a prominent differentially expressed gene in both breast and pancreatic cancer samples, and estrogen-related receptor alpha(ERR alpha) was found to link miR-1291 and CPT1C. MiR-1291 targeted ERR alpha and CPT1C was identified as a newly described ERR alpha target gene. Moreover, ERR alpha was found to influence cancer cell metabolism and proliferation, consistent with the cellular changes caused by miR-1291. Conclusion: This study demonstrated the existence and mechanism of action of a novel miR-1291-ERR alpha-CPT1C cancer metabolism axis that may provide new insights and strategies for the development of miRNA-based therapies for malignant cancers.