miR-28-5p promotes chromosomal instability in VHL-associated cancers by inhibiting Mad2 translation.
Chromosomal instability enables tumor development, enabled in part by aberrant expression of the mitotic checkpoint protein Mad2. Here we identify a novel regulatory mechanism for Mad2 expression involving miR-28-5p-mediated inhibition of Mad2 translation, and we demonstrate that this mechanism is triggered by inactivation of the tumor suppressor VHL, the most common event in clear cell renal cell carcinoma (ccRCC). In VHL-positive cancer cells, enhanced expression of miR-28-5p diminished Mad2 levels and promoted checkpoint weakness and chromosomal instability. Conversely, in checkpoint-deficient VHL-negative renal carcinoma cells, inhibition of miR-28-5p function restored Mad2 levels, mitotic checkpoint proficiency, and chromosomal stability. Notably, chromosome missegregation errors and aneuploidy that were produced in a mouse model of acute renal injury (as a result of kidney-specific ablation of pVHL function) were reverted in vivo also by genetic inhibition of miR-28-5p. Finally, bioinformatic analyses in human ccRCC associated loss of VHL with increased miR-28-5p expression and chromosomal instability. Together, our results defined miR-28-5p as a critical regulator of Mad2 translation and mitotic checkpoint function. By identifying a potential mediator of chromosomal instability in VHL-associated cancers, our work also suggests a novel microRNA-based therapeutic strategy to target aneuploid cells in VHL-associated cancers.
Authors' Affiliations: Institute of Molecular Health Sciences; and Rodent Center HCI, ETH Zurich, Zurich, Switzerland.
Michael P
MP
Hell
Claudio R
CR
Thoma
Niklaus
N
Fankhauser
Yann
Y
Christinat
Thomas C
TC
Weber
Wilhelm
W
Krek
D020413:3' Untranslated Regions; D000782:Aneuploidy; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D043171:Chromosomal Instability; D020090:Chromosome Segregation; D005260:Female; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism; D064246:Mad2 Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D010442:Peptide Chain Initiation, Translational; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
D020413:3' Untranslated Regions; C577697:MAD2L1 protein, human; C570628:MIRN28 microRNA, human; D064246:Mad2 Proteins; D035683:MicroRNAs; D034741:RNA, Small Interfering; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human