E3 Ubiquitin Ligase HRD1 Promotes Lung Tumorigenesis by Promoting Sirtuin 2 Ubiquitination and Degradation

Abstract

The NAD-dependent histone deacetylase sirtuin 2 (SIRT2) plays critical roles in mitosis and cell cycle progression and recently was shown to suppress tumor growth and to be downregulated in several types of cancers. However, the underlying mechanism of SIRT2 downregulation remains unknown. In this study, using bioinformatics, gene expression profiling, protein overexpression approaches, and cell migration assays, we showed that E3 ubiquitin ligase 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase degradation 1 (HRD1) interacts with SIRT2 and promotes its ubiquitination and degradation. Furthermore, we found that HRD1 deficiency induces SIRT2 upregulation and inhibits the growth and tumor formation of lung cancer cells both in vitro and in vivo. Of note, we observed that SIRT2 expression is downregulated in human lung cancer and also negatively correlates with HRD1 expression in these cancers. Additionally, we found that patients with lung adenocarcinoma having lower HRD1 or higher SIRT2 expression levels tend to survive longer. On the basis of these results, we propose a mechanism of lung tumorigenesis that involves HRD1-mediated downregulation of SIRT2 and suggest that interventions targeting HRD1 activity could be a potential therapeutic strategy to treat patients with lung cancer.

Integrative proteomics reveals the role of E3 ubiquitin ligase SYVN1 in hepatocellular carcinoma metastasis

“…Synoviolin (SYVN1), an evolutionarily conserved endoplasmic reticulum‐resident E3 ligase, is the central component of a complex facilitating degradation of misfolded proteins during the ubiquitin‐proteasome‐dependent process of endoplasmic reticulum‐associated degradation [ 14 , 15 ]. SYVN1 participates in biological events in several cancer types by regulating the ubiquitination and degradation of P53 [ 16 ], insulin‐like growth factor‐I receptor [ 17 ], and Sirtuin 2 [ 18 ]. Heat shock proteins (HSPs), which could help cancer cells survive and obtain an invasive phenotype, always function as molecular chaperones.…”

Emerging role of SIRT2 in non-small cell lung cancer (Review)

“…SIRT2 directly binds to transcription factor EB, to regulate acute shear stress-induced cell apoptosis by regulating the release of autophagy components and exosomes, which contributes to the suppression of tumorigenesis and the metastasis of NSCLC ( 71 ). A recent study demonstrated that SIRT2 was readily degraded via homologous recombination repair-mediated ubiquitination in NSCLC ( 67 ), supporting the anticancer function of SIRT2 in this disease.…”

“…Conflicting studies have nevertheless shown that SIRT2 expression is downregulated in NSCLC and that SIRT2 can inhibit tumor growth ( 49 , 67 ). Zhu et al ( 68 ) reported that deacetylation of aldo-keto reductase family 1 member C1 (AKR1C1) by SIRT2 inhibited the binding of AKR1C1 to STAT3, therefore decreasing the transcriptional activity of STAT3 and inhibiting migration of NSCLC cells.…”

Stabilization of SETD3 by deubiquitinase USP27 enhances cell proliferation and hepatocellular carcinoma progression

“…Ubiquitination assay was performed as previously described [ 35 ]. In brief, cells were lysed with a high concentration of SDS lysis buffer, denatured, immunoprecipitated with appropriate antibodies, and subjected to immunoblotting.…”