Cullin 3 Ubiquitin Ligases in Cancer Biology: Functions and Therapeutic Implications

Abstract

Cullin-RING ubiquitin ligases are the largest E3 ligase family in eukaryotes and are multiprotein complexes. In these complexes, the Cullin protein serves as a scaffold to connect two functional modules of the ligases, the catalytic subunit and substrate-binding subunit. To date, eight members of the Cullin family proteins have been identified. In the Cul3 ubiquitin ligases, Bric-a-brac/Tramtrack/Broad complex (BTB) domain-containing proteins function as a bridge to connect Cul3 and substrates. While the BTB domain is responsible for Cul3 binding, these proteins usually contain an additional domain for substrate interaction, such as MATH, kelch, Zn finger, and PAM, Highwire, and RPM-1 (PHR domain). With the existence of a large number of BTB proteins in human, the Cul3 ubiquitin ligases ubiquitinate a wide range of substrates involving in diverse cellular functions. In this review, we will discuss recent advances on the functions of Cul3 ubiquitin ligases in cancer development, progression, and therapeutic response and the dysregulation of Cul3-mediated ubiquitination events in human malignancies. In particular, we will focus on three Cul3 substrate adaptors, kelch-like ECH-associated protein (Keap1), kelch-like family member 20 (KLHL20), and speckle type BTB/POZ protein (SPOP), with the intent to highlight novel targets in cancer therapy.

Keywords: Cul3 ubiquitin ligases; KLHL20; Keap1; SPOP; cancer.

Figure 1

Summary of the functions and substrates of three Cul3 complexes in cancer. (Top) The Cul3–Keap1 ubiquitin ligase mediates Nrf2 degradation to suppress antioxidant responses, which plays dual roles in cancer initiation and progression. (Middle) The Cul3–KLHL20 ubiquitin ligase mediates the degradation of tumor-suppressor proteins PML and DAPK, thereby promoting tumor progression and therapy resistance. (Bottom) The Cul3–SPOP ubiquitin ligase possesses context-dependent tumor-promoting or -inhibiting role by regulating the degradation of multiple substrates.