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.