MARCHF1-mediated SULF1 degradation blocks THBS2/TGF-β/SMAD2/3 signaling to reverse colon cancer metastasis and 5-FU resistance.

Colon cancer (CC) is a common and fatal malignancy with a poor prognosis, primarily due to difficulties in early detection and chemotherapy resistance. This study investigates the role of heparan sulfate 6-O-endosulfatase 1 (SULF1) in CC cell proliferation, migration, apoptosis, and invasion. Through clinical samples and CC cell lines, we found that SULF1 promotes cell proliferation and survival, while inhibiting apoptosis, migration, and invasion. SULF1 interacts with thrombospondin-2 (THBS2) to regulate the transforming growth factor β 1 (TGF-β1)/SMAD family member 2/3 (SMAD2/3) pathway, promoting tumor progression. Membrane associated ring-CH-type finger 1 (MARCHF1) inhibits SULF1 function by accelerating its degradation, thereby suppressing CC cell growth and metastasis. Moreover, SULF1 silencing enhances sensitivity to 5-fluorouracil (5-FU) chemotherapy. In conclusion, targeting SULF1 and its regulatory network may provide new therapeutic strategies for CC.