UDP-glucose dehydrogenase supports autophagy-deficient PDAC growth via increasing hyaluronic acid biosynthesis

Autophagy is an essential degradation and recycling process that maintains cellular homeostasis during stress or nutrient deprivation. However, certain types of tumors such as pancreatic cancers can circumvent autophagy inhibition to sustain growth. The mechanism that autophagy-deficient pancreatic ductal adenocarcinoma (PDAC) uses to grow under nutrient deprivation is poorly understood. Our data show that nutrient deprivation in PDAC results in UDP-glucose dehydrogenase (UGDH) degradation, which is dependent on autophagic cargo receptor sequestosome 1 (p62). Moreover, we demonstrate that accumulated UGDH is indispensable for autophagy-deficient PDAC cells proliferation by promoting hyaluronic acid (HA) synthesis upon energy deprivation. Using an orthotopic mouse model of PDAC, we find that inhibition of HA synthesis by targeting UGDH in PDAC reduces tumor weight. Thus, the combined inhibition of HA and autophagy might be an attractive strategy for PDAC treatment. [Display omitted] •UGDH is degraded by autophagic process dependent on p62•Autophagy-deficient PDAC upregulates UGDH to promote hyaluronic acid synthesis•Hyaluronic acid maintains autophagy-deficient PDAC proliferation under nutrient starvation Fan et al. report that UGDH is degraded by p62-mediated autophagy, and it accumulates in autophagy-deficient PDAC. UGDH increases hyaluronic acid (HA) synthesis to sustain proliferation of autophagy-deficient PDAC. The combined inhibition of UGDH/HA with autophagy results in reduction of PDAC growth.