LncRNA-MIF, a c-Myc-activated long non-coding RNA, suppresses glycolysis by promoting Fbxw7-mediated c-Myc degradation.

The c-Myc proto-oncogene is activated in more than half of all human cancers. However, the precise regulation of c-Myc protein stability is unknown. Here, we show that the lncRNA-MIF (c-Myc inhibitory factor), a c-Myc-induced long non-coding RNA, is a competing endogenous RNA for miR-586 and attenuates the inhibitory effect of miR-586 on Fbxw7, an E3 ligase for c-Myc, leading to increased Fbxw7 expression and subsequent c-Myc degradation. Our data reveal the existence of a feedback loop between c-Myc and lncRNA-MIF, through which c-Myc protein stability is finely controlled. Additionally, we show that the lncRNA-MIF inhibits aerobic glycolysis and tumorigenesis by suppressing c-Myc and miR-586.

Zhang P ，Cao L ，Fan P ，Mei Y ，Wu M ... -  《-》

Guttiferone K impedes cell cycle re-entry of quiescent prostate cancer cells via stabilization of FBXW7 and subsequent c-MYC degradation.

Xi Z ，Yao M ，Li Y ，Xie C ，Holst J ，Liu T ，Cai S ，Lao Y ，Tan H ，Xu HX ，Dong Q ... -  《Cell Death & Disease》

MYC is a critical target of FBXW7.

Sato M ，Rodriguez-Barrueco R ，Yu J ，Do C ，Silva JM ，Gautier J ... -  《Oncotarget》

Recombinant human adenovirus-p53 injection induced apoptosis in hepatocellular carcinoma cell lines mediated by p53-Fbxw7 pathway, which controls c-Myc and cyclin E.

Tu K ，Zheng X ，Zhou Z ，Li C ，Zhang J ，Gao J ，Yao Y ，Liu Q ... -  《PLoS One》

CRL2(KLHDC3) and CRL1(Fbxw7) cooperatively mediate c-Myc degradation.

c-Myc is a proto-oncoprotein that regulates various cellular processes and whose abnormal expression leads to tumorigenesis. c-Myc protein stability has been shown to be predominantly controlled by the ubiquitin ligase (E3) CRL1Fbxw7 in a manner dependent on glycogen synthase kinase 3 (GSK3)-mediated phosphorylation. Here we show that, in some types of cancer cells, c-Myc degradation is largely insensitive to the GSK3 inhibitor (GSK3i) CHIR99021, suggesting the existence of an E3 other than CRL1Fbxw7 for c-Myc degradation. Mass spectrometry identified CRL2KLHDC3 as such an E3. In GSK3i-insensitive cancer cells, combined depletion of Fbxw7 and KLHDC3 resulted in marked stabilization of c-Myc, suggestive of a cooperative action of Fbxw7 and KLHDC3. Furthermore, transplantation of such cells deficient in both Fbxw7 and KLHDC3 into immunodeficient mice gave rise to larger tumors compared with those formed by cells lacking only Fbxw7. GSK3i-insensitive pancreatic cancer cells expressed lower levels of SHISA2, a negative regulator of the Wnt signaling pathway, than did GSK3i-sensitive cells. KLHDC3 mRNA abundance was associated with prognosis in pancreatic cancer patients with a low level of SHISA2 gene expression. These results suggest that KLHDC3 cooperates with Fbxw7 to promote c-Myc degradation in a subset of cancer cells with low GSK3 activity.

Motomura S ，Yumimoto K ，Tomonaga T ，Nakayama KI ... -  《-》