The roles of KLHL family members in human cancers

Abstract

The Kelch-like (KLHL) family members consist of three domains: bric-a-brac, tramtrack, broad complex/poxvirus and zinc finger domain, BACK domain and Kelch domain, which combine and interact with Cullin3 to form an E3 ubiquitin ligase. Research has indicated that KLHL family members ubiquitinate target substrates to regulate physiological and pathological processes, including tumorigenesis and progression. KLHL19, a member of the KLHL family, is associated with tumorigenesis and drug resistance. However, the regulation and cross talks of other KLHL family members, which also play roles in cancer, are still unclear. Our review mainly explores studies concerning the roles of other KLHL family members in tumor-related regulation to provide novel insights into KLHL family members.

Keywords: E3 ubiquitin ligase; Kelch-like family member; degradation; human cancer; ubiquitination.

Figure 1

A: The Diagram of 42 KLHL family members with Amino acid numbers are listed on the right. B: The structural components of the Cullin3-RING-KLHLs complex and its ability to regulate tumor occurrence and development. A. Kelch-like protein family members (KLHLs) consist of the bric-a-brac, tramtrack, broad complex (BTB)/poxvirus and zinc finger (POZ) domain, the BACK domain and the Kelch repeated domain, the BTB/POZ domain is responsible for binding cullin3, the Kelch domain determines substrates recruitment, and the BACK domain forms a linker between BTB domain and Kelch domain. Data comes from the Uniprot and the Smart databases. B. The Cullin3-RBX1-KLHLs complex consists of three components, including the Cullin3 protein functioning as the scaffold protein, the KLHLs protein responsible for identifying the targeted substrates and binding the Cullin3 protein, and the RING-box protein crucial to recruitment to E2. The KLHLs have the abilities of triggering several substrates ubiquitination modification to influence its stability and localization, thereby taking part in the regulation of tumor occurrence and development.

Figure 2

The Role of KLHLs in signaling pathways in cancer. The abnormity of signaling pathways is always closely related to tumor occurrence and development. KLHLs, as substrate adaptor proteins of Cullin3 E3 ligases, are involved in the occurrence and development of several types of cancers and regulates various signal pathways, including the PI3K/AKT pathway, mTOR signaling, Wnt/β-catenin signaling, NF-κB signaling, hippo signaling and autophagy-lysosome pathway.

Figure 3

The Role of KLHLs in cancers. KLHLs are involved in the occurrence and progression of a variety of tumors via promoting ubiquitination of a series of substrate proteins, including NRF2, Myosin 9b, SOX9, ACLY, PD-1, PML, DAPK, C/EBPs, p53, CDK2, UCK1 and ARHGEF7.