Functional divergence of PAPS synthases uncovers selective dependency on PAPSS1 in cancer

Ko-Chien Chen, MS (Advisor: Ronald DePinho, MD)

          Functional redundancy among paralogous enzymes is often presumed, yet whether this assumption holds true in cancer remains unclear. Here, we reveal non-redundant and opposing roles for the sulfation paralogues PAPSS1 and PAPSS2, which generate 3′-phosphoadenosine 5′-phosphosulfate (PAPS), the universal sulfate donor required for post-translational sulfation. Genomic analyses of human cancers uncover frequent co-deletion of PAPSS2 with PTEN, while PAPSS1 is consistently retained. Despite shared enzymatic activity, our data show that PAPSS1 is essential for tumor initiation and progression, whereas PAPSS2 supports early outgrowth but ultimately constrains tumor progression, in part through enhanced immune surveillance. Notably, tumors that escape dependency on PAPS synthases adopt an anaplerotic, redox-stressed state, thereby revealing a secondary metabolic vulnerability. These findings overturn the assumption of paralogue equivalence, position PAPSS1 as a key sulfation enzyme sustaining oncogenesis, and highlight dual therapeutic opportunities in sulfation-deficient cancers.

Advisory Committee

• Ronald DePinho, MD, Chair
• Simona Colla, PhD
• Daniel Frigo, PhD
• Matthew Gubin, PhD
• Traver hart, PhD
• Florian Müller, PhD