Phosphorylation by IKKβ Promotes the Degradation of HMGCL via NEDD4 in Lung Cancer

• DOI: 10.7150/ijbs.82015
• Publication Date: 2023-03-13T01:54:32Z
• Authors: Chenxi Zhong; Guosheng Xiong; Haitang Yang; Xiaohua Du; Jiankui Du; Feng Yao; Wentao Fang; Yuezhen Deng
• Keywords: Inflammation; Mice; Lung Neoplasms; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases; Ubiquitination; Animals; Lyases; Phosphorylation; Protein Serine-Threonine Kinases; 3. Good health; Research Paper; I-kappa B Kinase

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 catalyzes catabolism leucine promotes synthesis ketone bodies, was downregulated in lung cancer.Downregulation HMGCL associated with a larger tumor size shorter overall survival time.In functional overexpression increased content β-hydroxybutyrate (β-HB) inhibited tumorigenicity cells, deletion promoted de novo tumorigenesis KP (Kras G12D ;P53 f/f ) mice.Mechanistically, necrosis factor α (TNFα) treatment decreased protein level, IKKβ interacted phosphorylated it at Ser258, which destabilized HMGCL.Moreover, NEDD4 identified as E3 ligase for its degradation.In addition, mutation Ser258 to alanine ubiquitination by thus anchorage-independent growth cells more efficiently than did wild-type HMGCL.In summary, study demonstrated link between TNFα-mediated metabolism.