SUMO-Activating Enzyme Subunit 1 (SAE1) Is a Promising Diagnostic Cancer Metabolism Biomarker of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most diagnosed malignancies and a leading cause of cancer-related mortality globally. This is exacerbated by its highly aggressive phenotype, and limitation in early diagnosis and effective therapies. The SUMO-activating enzyme subunit 1 (SAE1) is a component of a heterodimeric small ubiquitin-related modifier that plays a vital role in SUMOylation, a post-translational modification involving in cellular events such as regulation of transcription, cell cycle and apoptosis. Reported overexpression of SAE1 in glioma in a stage-dependent manner suggests it has a probable role in cancer initiation and progression. In this study, hypothesizing that SAE1 is implicated in HCC metastatic phenotype and poor prognosis, we analyzed the expression of SAE1 in several cancer databases and to unravel the underlying molecular mechanism of SAE1-associated hepatocarcinogenesis. Here, we demonstrated that SAE1 is over-expressed in HCC samples compared to normal liver tissue, and this observed SAE1 overexpression is stage and grade-dependent and associated with poor survival. The receiver operating characteristic analysis of SAE1 in TCGA−LIHC patients (n = 421) showed an AUC of 0.925, indicating an excellent diagnostic value of SAE1 in HCC. Our protein-protein interaction analysis for SAE1 showed that SAE1 interacted with and activated oncogenes such as PLK1, CCNB1, CDK4 and CDK1, while simultaneously inhibiting tumor suppressors including PDK4, KLF9, FOXO1 and ALDH2. Immunohistochemical staining and clinicopathological correlate analysis of SAE1 in our TMU-SHH HCC cohort (n = 54) further validated the overexpression of SAE1 in cancerous liver tissues compared with ‘normal’ paracancerous tissue, and high SAE1 expression was strongly correlated with metastasis and disease progression. The oncogenic effect of upregulated SAE1 is associated with dysregulated cancer metabolic signaling. In conclusion, the present study demonstrates that SAE1 is a targetable cancer metabolic biomarker with high potential diagnostic and prognostic implications for patients with HCC.

The Role of Protein SUMOylation in Human Hepatocellular Carcinoma: A Potential Target of New Drug Discovery and Development

“…This indicates that the SUMOs protein plays an essential role in the development of HCC and suggests the potential of SUMOs as future targets. These data and Jiann’s research results are mutually corroborating, implying the potential of SUMOs as prognostic markers of HCC [ 48 ].…”

“…At present, there have been studies expounding the possible clinical applications of SUMOs protein. In the study of Jiann et al [ 48 ], it was found that the mRNA levels of SAE1 in liver cancer tumour tissues were significantly upregulated ( p < 0.0001). Patients with higher SAE1 mRNA have a worse disease survival rate (DSS) and progression-free survival rate (PFS).…”

RANBP2 Activates O-GlcNAcylation through Inducing CEBPα-Dependent OGA Downregulation to Promote Hepatocellular Carcinoma Malignant Phenotypes

“…SUMO is crucial for various types of cancer due to its reversible nature in cell cycle progression and genome integrity [ 34 ]. Apart from RANBP2, multiple SUMO enzymes are responsible for cancer progression and represent targetable cancer metabolic biomarkers [ 35 , 36 ]. In the current study, the immunofluorescence study indicated that CEBPα mostly resides in nuclei as a typical transcriptional factor.…”

Antrodia cinnamomea exerts an anti-hepatoma effect by targeting PI3K/AKT-mediated cell cycle progression in vitro and in vivo

“…SAE1 is a component of a heterodimeric small ubiquitin-related modifier that plays a vital role in SUMOylation, a post-translational modification involving in cellular events such as regulation of transcription, cell cycle and apoptosis. A recent study showed that SAE1 was overexpressed in HCC, and its overexpression was stage and grade-dependent and associated with poor survival 37 . TOP2A is one of the tumor drivers in a myriad of malignant tumors, and it increased cancer cell proliferation through inhibiting P53 activity 38 .…”