The E3 ligase HECTD3 promotes esophageal squamous cell carcinoma (ESCC) growth and cell survival through targeting and inhibiting caspase-9 activation.

Apoptosis resistance is an acquired hallmark of cancer cells and many factors can contribute to the tumor cell apoptosis resistance. In this study, we demonstrated that HECTD3, overexpressed in human esophageal squamous cell carcinoma (ESCC), confers cells resistance to cisplatin-induced apoptosis and promotes cancer cell survival. HECTD3 can bind and ubiquitinate caspase-9, which leads to inhibiting caspase-9 oligomerization and association with Apaf-1, and results in suppressing caspase-9 activation and inhibiting apoptosis. Furthermore, this antiapoptotic function of HECTD3 is dependent on its Thr-157 phosphorylation by ERK. HECTD3, but not T157A mutant, facilitates cell survival in ESCC cells in survival assay in vitro and promotes tumor growth in a xenograft mouse model in vivo. These findings establish a new mechanism of cancer cell resistance to apoptosis and provide a new potential strategy for ESCC treatment.