3D imaging of pancreas hyperplasia

Axel Behrens : The ubiquitin system in cancer

Standard content

The ubiquitin system affects many cancer signalling pathways by controlling the stability of specific proteins. We hope that understanding exactly how this system is corrupted in tumours will identify new therapeutic targets.

Fbw7 (also known as Fbxw7, Ago, Cdc4, Sel10) is the substrate recognition component of a Skp1-Cul1-F-box (SCF)-type E3 ubiquitin ligase that targets several oncoproteins including c-Jun, c-Myc and NICD1 for K48-linked ubiquitination and proteasomal degradation. We have demonstrated important functions of Fbw7 in intestinal and neural stem cells (Hoeck et al., 2010; Sancho et al., 2010), and because it controls the stability of important oncoproteins, Fbw7 is one of the most commonly mutated tumour suppressors in human cancers.

In our ongoing efforts to understand tissue-specific roles of Fbw7, we recently found that mice expressing oncogenic Ras in combination with Fbw7 inactivation develop lung squamous cell carcinomas (LSCC), a common tumour type which accounts for about 30% of all lung cancers, and we used this mouse model to identify a novel treatment strategy for LSCC (unpublished).

In intestinal tumour models, we found that the E3 ubiquitin ligase Fbw7 and the deubiquitylase USP28 show direct and specific antagonism (Diefenbacher et al., 2015), qualifying USP28 as a potential therapeutic cancer target. In line with this notion, my laboratory has shown that inactivation of USP28 in established intestinal tumours results in tumour regression (Diefenbacher et al., 2014).

To better understand the regulation of Fbw7 itself, we have performed several genetic and biochemical screens. This work identified USP9X as a key regulator of Fbw7 function in intestinal cancer (Khan et al., 2018).Further analysis of these data is hoped to pinpoint novel therapeutic targets for personalised treatment of Fbw7-deficient tumours.