The Oncogenic MicroRNA-21 Inhibits the Tumor Suppressive Activity of FBXO11 to Promote Tumorigenesis

• Published in: The Journal of biological chemistry Vol. 290; no. 10; pp. 6037 - 6046
• Main Authors: Yang, Chuan He, Pfeffer, Susan R., Sims, Michelle, Yue, Junming, Wang, Yinan, Linga, Vijay G., Paulus, Elena, Davidoff, Andrew M., Pfeffer, Lawrence M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.03.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Apoptosis - genetics; cancer; Carcinogenesis - genetics; Cell Proliferation - genetics; F-Box Proteins - genetics; F-Box Proteins - metabolism; FBXO11; Gene Expression Regulation, Neoplastic; glioblastoma; Glioblastoma - genetics; Glioblastoma - pathology; Humans; Male; melanoma; Melanoma - genetics; Melanoma - pathology; Mice; microRNA (miRNA); MicroRNAs - biosynthesis; miR-21; Molecular Bases of Disease; Molecular Targeted Therapy; prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; tumor suppressor gene; prostate cancer; glioblastoma; microRNA (miRNA); melanoma; cancer; miR-21; FBXO11; tumor suppressor gene
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.632125

The microRNA miR-21 is overexpressed in most human cancers and accumulating evidence indicates that it functions as an oncogene. Since miRNAs suppress the expression of their target genes, we hypothesized that some miR-21 targets may act as tumor suppressors, and thus their expression would be anticipated to be reduced by the high miR-21 levels observed in various human cancers. By microarray analysis and quantitative PCR we identified and validated FBXO11 (a member of the F-box subfamily lacking a distinct unifying domain) as a miR-21 target gene. FBXO11 is a component of the SKP1-CUL1-F-box ubiquitin ligase complex that targets proteins for ubiquitination and proteosomal degradation. By loss of function and gain of function studies, we show that FBXO11 acts as a tumor suppressor, promotes apoptosis and mediates the degradation of the oncogenic protein BCL6. The critical role that FBXO11 plays in miR-21-mediated tumorigenesis was demonstrated by a rescue experiment, in which silencing FBXO11 in miR-21KD cancer cells restored their high tumorigenicity. Expression of miR-21 and FBXO11 are inversely correlated in tumor tissue, and their expression correlates with patient survival and tumor grade. High FBXO11 expression correlates with better patient survival and lower tumor grade consistent with its tumor suppressor activity. In contrast high miR-21 expression, which correlates with poor patient survival and higher tumor grade, is consistent with its oncogenic activity. Our results identify FBXO11 as a novel miR-21 target gene, and demonstrate that the oncogenic miRNA miR-21 decreases the expression of FBXO11, which normally acts as a tumor suppressor, and thereby promotes tumorigenesis. Background: miR-21 is overexpressed in many human cancers. Results: FBXO11 (a member of the F-box subfamily lacking a distinct unifying domain) is a novel miR-21 target gene, and inhibits tumorigenesis. Conclusion: miR-21 down-regulates FBXO11 which acts as a tumor suppressor in melanoma, prostate cancer and glioblastoma. Significance: FBXO11 may have promise as a therapeutic target, and as a diagnostic and prognostic marker in cancer.