JOSD1-mediated stabilization of SUFU controls pancreatic cancer progression.

The Hedgehog (Hh) signaling pathway plays an essential role in embryonic development, and its aberrant activation is associated with pancreatic cancer progression. However, the function of Suppressor of Fused (SUFU), a critical negative regulator of the Hh pathway, in pancreatic cancer has been poorly studied. In this study, we found that SUFU knockdown significantly inhibits pancreatic cancer cell growth, migration, and proliferation while inducing apoptosis. We identified a direct interaction between JOSD1 and SUFU, whereby JOSD1 stabilizes SUFU protein by inhibiting its ubiquitination and proteasomal degradation. Public database analyses revealed a positive correlation between JOSD1 and SUFU expression in pancreatic cancer tissues, and immunofluorescence staining of clinical samples further showed that JOSD1 and SUFU are co-localized and expressed at higher levels in pancreatic cancer tissues compared with normal pancreatic tissues. Notably, SUFU regulates pancreatic cancer cell behavior through a non-canonical, Hh-independent mechanism. Depletion of either JOSD1 or SUFU downregulated proliferation-related genes and upregulated apoptosis-related genes, thereby suppressing pancreatic cancer cell growth and promoting apoptosis, with these effects reversed by SUFU restoration. Consistently, silencing of JOSD1 or SUFU significantly attenuates tumor growth and reduces Ki67 expression in vivo, whereas re-expression of SUFU in JOSD1-deficient tumors restores tumor growth and proliferation. Collectively, these findings highlight the functional importance of JOSD1-mediated SUFU stabilization in pancreatic cancer and suggest potential therapeutic strategies targeting this axis.