Advances of E3 ligases in lung cancer

Abstract

Lung cancer is a leading cause of cancer-related death, and the most common type of lung cancer is non-small cell lung cancer, which accounts for approximately 85 % of lung cancer diagnoses. Recent studies have revealed that ubiquitination acts as a crucial part of the development and progression of lung cancer. The E1-E2-E3 three-enzyme cascade has a core function in ubiquitination, so targeted adjustments of E3 ligases could be used in lung cancer treatment. Hence, we elucidate research advances in lung cancer-related E3 ligases by briefly describing the structure and categorization of E3 ligases. Here, we provide a detailed review of the mechanisms by which lung cancer-related E3 ligases modify substrate proteins and regulate signaling pathways to facilitate or suppress cancer progression. We hope to show a new perspective on targeted precision therapy for lung cancer.

Keywords: E3 ligase; E3-targeting therapy; Lung cancer; Ubiquitination.

Fig. 1

Schematic diagram of the domain structures of E3 ubiquitin ligases. Approximate domain positions and molecular weights are provided. E3 ligases are usually divided into three main families: RING, HECT and RBR family. Members of RING family can be further divided into four subfamilies, including MARCH, PA-TM-RING, TRIM and UIM subfamily. HECT E3s are classified into three subfamilies: C2-WW-HECT, HERC, and ‘other’ HECT E3 ligases. TM, multiple transmembrane; PA, protease-associated domain; UIM, ubiquitin-interacting motif; BB, B-box domain; CC, coiled-coil domain; HECT, homologous to E6AP C-terminus; C2, Ca²⁺ domain; WW, tryptophan–tryptophan domain; RLD, regulator of chromatin condensation 1-like domain; SPRY, SPIA and ryanodine receptor domain; WD40, WD dipeptide domain; ZNF, zinc finger; DOC, APC10/DOC domain; ARM, armadillo repeat-containing domain; UBA, ubiquitin-associated domain; WWE, WWE domain; BH2, Bcl-2 homology 3 domain; BH3, Bcl-2 homology 3 domain; ANK, ankyrin-repeat domain; SUN, SAD1/UNC domain; PABC, Mademoiselle/PABC domain; AZUL, Zn-binding N-terminal domain; PHD, plant homeodomain-type zinc finger; AR, androgen receptor; IBR, in-between-RING; LDD, linear ubiquitin chain-determining domain; NZF, NPL4 zinc finger domain; PUB, PNGase/ubiquitin-associated domain; RBR, RING-in-Between-RING; RWD, RING finger and WD repeat-containing; TMD, transmembrane domain; UBA-L, ubiquitin associated-like domain; UBL, ubiquitin-like.

Fig. 2

The roles of E3 ubiquitin ligases in lung cancer. E3 ligases play an important role in the occurrence and progression of lung cancer and are involved in a variety of cellular biochemical processes including, thus having different functions and influence in cell proliferation, migration, cell cycle, invasion, apoptosis, autophagy, EMT and sensitivity to IR or drugs in lung cancer.

Fig. 3

Classification of E3 ligases in lung cancer according to oncogenic/tumor suppressor gene type.