Enhanced SLC35B2/SAV1 sulfation axis promotes tumor growth through inhibiting Hippo signaling in hepatocellular carcinoma

Background and Aims: Protein tyrosine sulfation (PTS) is a common post-translational modification that regulates a variety of physiological and pathological processes. However, the role of PTS in cancer remains poorly understood. The goal of this study was to determine whether and how PTS plays a role in HCC progression. Approach and Results: By mass spectrometry and bioinformatics analysis, we identified SAV1 as a novel substrate of PTS in hepatocellular carcinoma (HCC). Oxidative stress upregulates the transcription of SLC35B2, a Golgi-resident transporter of sulfate donor 3’-phosphoadenosine 5’-phosphosulfate, leading to increased sulfation of SAV1. Sulfation of SAV1 disrupts the formation of SAV1-MST1 complex, resulting in a decrease of MST1 phosphorylation and subsequent inactivation of Hippo signaling. These molecular events ultimately foster the growth of HCC cells both in vivo and in vitro . Moreover, SLC35B2 is a novel transcription target gene of the Hippo pathway, constituting a positive feedback loop that facilitates HCC progression under oxidative stress. Conclusions: Our findings reveal a regulatory mechanism of SLC35B2/SAV1 sulfation axis in response to oxidative stress, highlighting its potential as a promising therapeutic target for HCC.