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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most commonly diagnosed cancer and ranks as the third commonest cause of cancer-related mortality, accounting for more than 700,000 fatalities in the world, annually [1]
SAE1 Is Overexpressed in HCC and Associated with Disease Progression
Using the STRING database for visualization of probable network of SAE1-associated functional proteins in humans, we found that SAE1 exhibited strong interaction with small ubiquitinlike modifier (SUMO) proteins such as SAE2, SUMO-conjugating enzyme E2I (UBE2I/UBC9) and SUMO specific peptidase 1 (SENP1), neural precursor cell-expressed developmentally down-regulated protein 8 (NEDD8), ubiquitin-conjugating enzyme E2M (UBE2M), RAN GTPase-activating protein 1 (RANGAP1), RAN binding protein 2 (RANBP2), RWD domain containing protein 3 (RWDD3), cullin-4A (CUL4A), cullin-5 (CUL5), cullin-associated NEDD8-dissociated protein 1 (CAND1), RING-box protein 1 (RBX1), S-phase kinase-associated protein 1/2 (SKP1/2), and defective in cullin neddylation 1 domain-containing 1 (DCUN1D1) protein (Figure 5A)
Summary
Hepatocellular carcinoma (HCC) is the fifth most commonly diagnosed cancer and ranks as the third commonest cause of cancer-related mortality, accounting for more than 700,000 fatalities in the world, annually [1]. The last 5 decades has been characterized by discovery several biomarkers for diagnosis of HCC, including the α-fetoprotein (AFP), AFP-L3 (a heteroplast of AFP), des-γ-carboxyprothrombin (DCP), α-L-fucosidase (AFU), golgi protein 73 (GP73), osteopontin (OPN) and carbohydrate antigen 19-9 (CA19-9), which is globally regarded as diagnostic serological biomarkers for diagnosis of HCC patients. Due to the clonal evolution, intratumoral and interpatient heterogeneity of HCC [4,5], like AFP, the diagnostic validity and clinical applicability of all these serological biomarkers remain debatable, especially considering their sub-optimal diagnostic specificity and sensitivity for early detection of HCC [6,7]. Against the background of this diagnostic challenge, the discovery of a biomarker with high and reliable diagnostic and prognostic accuracy and validity remain an unmet need in hepato-oncology clinics. The exploration for such biomarker in the present study; with the ultimate aim of proffering a therapeutic target, as well as improving the accuracy of diagnosis and efficacy of treatment modality in patients with HCC
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