SAE1 emerges as a pan-cancer driver and key regulator of HCC metastasis.

INTRODUCTION

Dysregulation of SUMOylation is implicated in cancer progression. While the role of SUMO-activating enzyme (SAE) and its mechanisms in cancer remain unclear.

OBJECTIVES

We investigated the role of SAE subunit 1 (SAE1) in hepatocellular carcinoma (HCC) metastasis.

METHODS

We analyzed SAE1 expression across 28 pan-cancer subtypes. SAE1 complexes were identified and characterized using interactome analysis, Co-IP, immunofluorescence, and AlphaFold3 predictions. These findings were validated using in situ and vein tail injection xenograft mouse models, HCC organoids, and IHC using HCC tissue samples.

RESULTS

Increased SAE1 expression was correlated with poorer prognosis and higher driver gene mutation frequencies in six pan-cancers, particularly HCC. We identified a novel interaction between SAE1 and yin-yang 1 (YY1), where SAE1 enhances YY1 stability and activity, leading to Wnt3a transcription and subsequent activation of the Wnt pathway, eventually promoting cell migration and invasion. Moreover, a positive correlation between SAE1 and Wnt3a expression was confirmed in HCC organoids and HCC tissue samples.

CONCLUSION

This study established SAE1 as a novel independent prognostic biomarker in multiple cancers and identified its mechanistic role in HCC progression, suggesting its potential value for future translational research toward therapeutic development.