Title:Cullin-RING Ligases as Attractive Anti-cancer Targets
Volume: 19
Issue: 18
Author(s): Yongchao Zhao and Yi Sun
Affiliation:
Keywords:
Anticancer targets, autophagy, cullins, CRL/SCF E3 ligase, MLN4924, NEDD8, neddylation, protein degradation, ubiquitin,
UPS.
Abstract: The ubiquitin-proteasome system (UPS) promotes the timely degradation of short-lived proteins with key regulatory roles in a
vast array of biological processes, such as cell cycle progression, oncogenesis and genome integrity. Thus, abnormal regulation of UPS
disrupts the protein homeostasis and causes many human diseases, particularly cancer. Indeed, the FDA approval of bortezomib, the first
class of general proteasome inhibitor, for the treatment of multiple myeloma, demonstrated that the UPS can be an attractive anti-cancer
target. However, normal cell toxicity associated with bortezomib, resulting from global inhibition of protein degradation, promotes the
focus of drug discovery efforts on targeting enzymes upstream of the proteasome for better specificity. E3 ubiquitin ligases, particularly
those known to be activated in human cancer, become an attractive choice. Cullin-RING Ligases (CRLs) with multiple components are
the largest family of E3 ubiquitin ligases and are responsible for ubiquitination of ∼20% of cellular proteins degraded through UPS. Activity
of CRLs is dynamically regulated and requires the RING component and cullin neddylation. In this review, we will introduce the
UPS and CRL E3s and discuss the biological processes regulated by each of eight CRLs through substrate degradation. We will further
discuss how cullin neddylation controls CRL activity, and how CRLs are being validated as the attractive cancer targets by abrogating the
RING component through genetic means and by inhibiting cullin neddylation via MLN4924, a small molecule indirect inhibitor of CRLs,
currently in several Phase I clinical trials. Finally, we will discuss current efforts and future perspectives on the development of additional
inhibitors of CRLs by targeting E2 and/or E3 of cullin neddylation and CRL-mediated ubiquitination as potential anti-cancer agents.
