Phosphorylation by IKK8 Promotes the Degradation of HMGCL via NEDD4 in Cancer

Inflammation and metabolic reprogramming are hallmarks of cancer. How inflammation regulates cancer metabolism remains poorly understood. In this study, we found that 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL), the enzyme that catalyzes the catabolism of leucine and promotes the synthesis of ketone bodies, was downregulated in lung cancer. Downregulation of HMGCL was associated with a larger tumor size and a shorter overall survival time. In a functional study, overexpression of HMGCL increased the content of 8-hydroxybutyrate (8-HB) and inhibited the tumorigenicity of lung cancer cells, and deletion of HMGCL promoted de novo tumorigenesis in KP (KrasG12D;P53f/f) mice. Mechanistically, tumor necrosis factor alpha (TNF alpha) treatment decreased the HMGCL protein level, and IKK8 interacted with HMGCL and phosphorylated it at Ser258, which destabilized HMGCL. Moreover, NEDD4 was identified as the E3 ligase for HMGCL and promoted its degradation. In addition, mutation of Ser258 to alanine inhibited the ubiquitination of HMGCL by NEDD4 and thus inhibited the anchorage-independent growth of lung cancer cells more efficiently than did wild-type HMGCL. In summary, this study demonstrated a link between TNF alpha-mediated inflammation and cancer metabolism.

Automated summary

This study found that the downregulation of 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) in lung cancer was associated with larger tumor size and shorter overall survival time. Overexpression of HMGCL increased the content of 8-hydroxybutyrate (8-HB) and inhibited the tumorigenicity of lung cancer cells. Mechanistically, TNF alpha treatment decreased HMGCL protein level by phosphorylating it at Ser258 through IKK8, and NEDD4 promoted the degradation of HMGCL. These findings demonstrate a link between TNF alpha-mediated inflammation and cancer metabolism.