E3 ubiquitin ligase HECTD3 is a tumor suppressor and mediates the polyubiquitination of SLC7A11 to promote ferroptosis in colon cancer

Homologous to the E6-associated protein carboxyl terminus domain containing 3 (HECTD3) has been reported to play an essential role in biological processes, including drug resistance, metastasis or apoptosis. However, the relationships between HECTD3 and Colorectal cancer (CRC) remain to be unclear. In this study, we discovered that HECTD3 expressed lowly in CRC compared with normal tissues and patients with low HECTD3 suffered from poorer survival outcomes relative to those with high HECTD3 levels. HECTD3 inhibition could significantly enhance proliferative, clone abilities and self-renewal capacities of CRC cells in vitro and in vivo. Mechanistically, our findings revealed that HECTD3 had endogenous interactions with SLC7A11 proteins. HECTD3 promoted the polyubiquitination of SLC7A11 to trigger the degradation of SLC7A11 proteins. Targeting HECTD3 could notably prolong the half-life period of SLC7A11 proteins, thereby promoting its stability. However, the cysteine mutation at amino acid 823 (ubiquitinase active site) of HECTD3 impaired the polyubiquitination of SLC7A11. HECTD3 deficiency depended on accumulated SLC7A11 proteins to accelerate malignant progression of CRC in vitro and in vivo. Thus, HECTD3 could suppress SLC7A11 levels to attenuate the SLC7A11-mediated cystine uptake, leading to enhanced CRC ferroptosis. SLC7A11 inhibition through polyubiquitination by HECTD3 increased ferroptosis, thereby inhibiting CRC tumor growth. Taken together, these results showed that HECTD3 controlled the stability of SLC7A11 and uncovered the function of HECTD3/SLC7A11 axis in regulating CRC progression.