USP37 directly deubiquitinates and stabilizes c-Myc in lung cancer

Abstract

The oncoprotein c-Myc is frequently overexpressed in many cancers and is essential for cancer cell proliferation. Ubiquitin-proteasome-dependent degradation is one of the main ways in which cells control c-Myc abundance at a post-translational level. However, the underlying mechanism by which c-Myc is directly deubiquitinated is not fully understood. In this study, by screening ubiquitin-specific proteases (USPs) that may regulate c-Myc stability, we identified USP37 as a novel deubiquitinating enzyme (DUB) that stabilizes c-Myc via direct binding. The overexpression of USP37 markedly increases c-Myc abundance by blocking its degradation, whereas the depletion of USP37 promotes c-Myc degradation and reduces c-Myc levels. Further studies indicate that USP37 directly interacts with c-Myc and deubiquitinates c-Myc in a DUB activity-dependent manner. Functionally, USP37 regulates cell proliferation and the Warburg effect by regulating c-Myc levels. Clinically, USP37 is significantly upregulated in human lung cancer tissues, where its expression is positively correlated with c-Myc protein expression. Thus, our findings uncover a previously unrecognized role for USP37 in the regulation of c-Myc stability in lung cancer and suggest that USP37 might be a potential therapeutic target for the treatment of lung cancer.

Uncovering the SUMOylation and ubiquitylation crosstalk in human cells using sequential peptide immunopurification

“…While the ubiquitylation status of H2B is critical for the transcriptional process34, the function of H2B SUMOylation is presently unknown. Although USP22 is the only deubiquitinating enzyme for which we saw a reciprocal effect, we noted a similar behaviour for USP37 and its substrate c-Myc35 (Supplementary Fig. 11).…”

Expression of c-myc and mutation of the KRAS gene in patients with ovarian mucinous tumors

“…c-myc protein is positively expressed in gastric cancer, bladder cancer, testicular cancer, pituitary tumors, and endometrial cancer, among others, and is related to their staging, classification, size, and patient age (Huang et al, 2014;Li et al, 2014;Pan et al, 2015;Ishak et al, 2015). Recently, the c-myc gene was reported to be amplified in patients with early-stage ovarian cancer, which was associated with prognosis (Di et al, 2013).…”

Deubiquitinating c-Myc: USP36 steps up in the nucleolus

“…59 Interestingly, USP37 regulation of Myc does not require either Fbw7 or the phosphorylation of Myc at T58. Instead, it directly interacts with Myc at the MBIII region.…”

“…Functionally, USP37 promotes cell proliferation and metabolism by stabilizing Myc and it is also overexpressed in tested human lung cancers. 59 Whether the activity of USP37 coordinates with that of USP28 requires further study.…”