The emerging role for Cullin 4 family of E3 ligases in tumorigenesis

Abstract

As a member of the Cullin-RING ligase family, Cullin-RING ligase 4 (CRL4) has drawn much attention due to its broad regulatory roles under physiological and pathological conditions, especially in neoplastic events. Based on evidence from knockout and transgenic mouse models, human clinical data, and biochemical interactions, we summarize the distinct roles of the CRL4 E3 ligase complexes in tumorigenesis, which appears to be tissue-and context-dependent. Notably, targeting CRL4 has recently emerged as a noval anti-cancer strategy, including thalidomide and its derivatives that bind to the substrate recognition receptor cereblon (CRBN), and anticancer sulfonamides that target DCAF15 to suppress the neoplastic proliferation of multiple myeloma and colorectal cancers, respectively. To this end, PROTACs have been developed as a group of engineered bi-functional chemical glues that induce the ubiquitinationmediated degradation of substrates via recruiting E3 ligases, such as CRL4 (CRBN) and CRL2 (pVHL). We summarize the recent major advances in the CRL4 research field towards understanding its involvement in tumorigenesis and further discuss its clinical implications. The anti-tumor effects using the PROTAC approach to target the degradation of undruggable targets are also highlighted.

<p>RING Finger Protein 38 Mediates LIM Domain Binding 1 Degradation and Regulates Cell Growth in Colorectal Cancer</p>

“…5 At present, the research and development of new drugs targeting E3 ubiquitin ligase have become a research hotspot of scientists. 6 Therefore, the study of ubiquitination of proteins in colorectal cancer (CRC) cells is of great significance for the treatment of colorectal cancer caused by the disorder of ubiquitin system. RNF38, the ring finger protein 38, belongs to one of the largest E3 ubiquitin ligase family proteins.…”

Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery

“…72,73 Much evidence has proved that DCAF15 is the main target of anticancer sulfonamides. In addition, the E3 ligase DCAF15 belongs to the CUL4A/B family, just like CRBN, 74 and they show similar chemical modulation, which suggests that transforming sulfonamides into bifunctional PROTACs is a potential direction through recruiting the DCAF15 E3 ligase. 75…”

Patent Highlights June–July 2019

“…This allows selective degradation of key proteins that would be difficult to target without severe side effects using conventional approaches. Utilizing DCAF15 (an adaptor protein of an E3 ligase complex) as a recruiting moiety in PROTACs is attractive for cancer drug development [13]. Disclosed by this invention are methods of degrading proteins from the BET, BTK and EGFR families which control specific networks of genes involved in cellular proliferation and in cell cycle progression or play an important role in epigenetics.…”