Ubiquitylation of unphosphorylated c-myc by novel E3 ligase SCF^Fbxl8

Abstract

Overexpression of c-myc via increased transcription or decreased protein degradation is common to many cancer etiologies. c-myc protein degradation is mediated by ubiquitin-dependent degradation, and this ubiquitylation is regulated by several E3 ligases. The primary regulator is Fbxw7, which binds to a phospho-degron within c-myc. Here, we identify a new E3 ligase for c-myc, Fbxl8 (F-box and Leucine Rich Repeat Protein 8), as an adaptor component of the SCF (Skp1-Cullin1-F-box protein) ubiquitin ligase complex, for selective c-myc degradation. SCF Fbxl8 binds and ubiquitylates c-myc, independent of phosphorylation, revealing that it regulates a pool of c-myc distinct from SCF Fbxw7 . Loss of Fbxl8 increases c-myc protein levels, protein stability, and cell division, while overexpression of Fbxl8 reduces c-myc protein levels. Concurrent loss of Fbxl8 and Fbxw7 triggers a robust increase in c-myc protein levels consistent with targeting distinct pools of c-myc. This work highlights new mechanisms regulating c-myc degradation.

SCF‐FBXL8 contributes to liver metastasis and stem‐cell‐like features in colorectal cancer cells by mediating ubiquitination and degradation of TP53

“…FBXL8 plays an important role in the pathological mechanism of a few tumours. 21 , 22 We explored the effect of FBXL8 on the pathological process of CRC. FBXL8 KO or FBXL8 ΔFbox, FBXL8 ΔLRR plasmids were transfected into HT29 and HCT116 cells, and the level of p53 was detected by western blotting.…”

“…FBXL8 plays an important role in the pathological mechanism of a few tumours 21,22 . We explored the effect of FBXL8 on the pathological process of CRC.…”

“… 20 It has also been proved that the F‐box region of FBXL8 can interact with the SCF complex, thus playing an important role in ubiquitination and degradation of downstream proteins. 21 , 22 However, FBXL8 has been less reported in CRC. We hypothesized that FBXL8 degrades the tumour suppressor gene P53 through ubiquitination, leading to the pathological progression of CRC.…”

“…In vitro analysis of 1349 matched breast cancer tissues showed that FBXL8 promoted cell survival and tumourigenesis, and its level increased with BRCA progression 20 . It has also been proved that the F‐box region of FBXL8 can interact with the SCF complex, thus playing an important role in ubiquitination and degradation of downstream proteins 21,22 . However, FBXL8 has been less reported in CRC.…”