The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders

Abstract

The HECT (Homologous to the E6-AP Carboxyl Terminus)-family protein E6AP (E6-associated protein), encoded by the UBE3A gene, is a multifaceted ubiquitin ligase that controls diverse signaling pathways involved in cancer and neurological disorders. The oncogenic role of E6AP in papillomavirus-induced cancers is well known, with its action to trigger p53 degradation in complex with the E6 viral oncoprotein. However, the roles of E6AP in non-viral cancers remain poorly defined. It is well established that loss-of-function alterations of the UBE3A gene cause Angelman syndrome, a severe neurodevelopmental disorder with autosomal dominant inheritance modified by genomic imprinting on chromosome 15q. Moreover, excess dosage of the UBE3A gene markedly increases the penetrance of autism spectrum disorders, suggesting that the expression level of UBE3A must be regulated tightly within a physiologically tolerated range during brain development. In this review, current the knowledge about the substrates of E6AP-mediated ubiquitination and their functions in cancer and neurological disorders is discussed, alongside with the ongoing efforts to pharmacologically modulate this ubiquitin ligase as a promising therapeutic target.

Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

“…HECT E3 ligases are associated with many types of human cancers, but discovery of small-molecule inhibitors for these targets has been limited, partly due to the poorly-characterized binding surfaces of HECT E3s [ 229 ]. WWP2 (WW domain-containing E3 Ub protein ligase 2) is a NEDD4-family HECT E3 ligase that can cause degradation of tumor suppressor proteins PTEN and Oct4 in many cancers [ 230 ].…”

“…E6AP (E6-associated protein) is a HECT with well-documented roles in human papillomavirus (HPV)- and hepatitis C virus (HCV)-induced cancers. For example, E6AP can be hijacked by viral E6 protein to target p53 and/or retinoblastoma protein (Rb) for proteasomal degradation, contributing to the development of malignancies [ 229 ]. Some small-molecule inhibitors targeting the E6AP–p53 interaction have been identified, such as compound 12 [ 185 ], which was shown to rescue p53 function and inhibit proliferation of HPV infected cells.…”

Oncogenic UBE3C promotes breast cancer progression by activating Wnt/β-catenin signaling

“…E3 ligases play critical roles in the regulation of multiple biological signals via selectively binding to their specific protein substrates [ 18 , 23 ]. Dysregulation of the HECT E3 ligase contributes to various pathological disorders, including human cancers [ 24 – 26 ]. E6AP, the first identified member of the HECT E3 family [ 27 ], targets the tumor suppressor TP53 through ubiquitin-mediated proteolysis, which enhances the degradation of the TP53 protein and leads to the progression of various human cancers [ 24 ].…”

“…Dysregulation of the HECT E3 ligase contributes to various pathological disorders, including human cancers [ 24 – 26 ]. E6AP, the first identified member of the HECT E3 family [ 27 ], targets the tumor suppressor TP53 through ubiquitin-mediated proteolysis, which enhances the degradation of the TP53 protein and leads to the progression of various human cancers [ 24 ]. UBE3C, another member of the HECT E3 family, has been reported to play a critical role in multiple cancers [ 8 – 10 ].…”

Exploring the Roles of HERC2 and the NEDD4L HECT E3 Ubiquitin Ligase Subfamily in p53 Signaling and the DNA Damage Response

“…Over the past two decades, HECT-related cancer research has focused on the founding member of the HECT E3 ligase family, E6 associate protein (E6AP) (25)(26)(27)(28)(29)(30). There are many studies that have cemented E6AP as a critical regulator of biochemical processes involved in the development of cervical and prostate cancer.…”