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

Abstract

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 β-hydroxybutyrate (β-HB) and inhibited the tumorigenicity of lung cancer cells, and deletion of HMGCL promoted de novo tumorigenesis in KP (Kras G12D ;P53 f/f ) mice. Mechanistically, tumor necrosis factor α (TNFα) treatment decreased the HMGCL protein level, and IKKβ 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 TNFα-mediated inflammation and cancer metabolism.

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“…TNF-α can activate the IKK complex (IKK-α, IKk-β, and IKk-γ) by binding to the TNF receptor (TNFR). Induction of phosphorylation and degradation of IκB, activation of NF-κB, and nuclear translocation, ultimately lead to inflammation 35 . Liu et al found that the serum TNF-α content in children with RV enteritis increased significantly, indicating that TNF-α was involved in the process of RV enteritis 36 .…”

TRIM22 induces cellular senescence by targeting PHLPP2 in hepatocellular carcinoma

“…It is reported that TRIM22 overexpression increases the phosphorylation of IKKβ at S181 and Y188, resulting in IKKβ activation [ 53 ]. Activated IKKβ induces the phosphorylation and subsequent degradation of substrates by recruiting E3 ligases [ 54 , 55 ]. Consistent with these previous reports, we observed that PHLPP2 was phosphorylated by IKKβ activation in TRIM22-overexpressed cells, which is crucial for the recruitment of TRIM22.…”

Advances of E3 ligases in lung cancer

“…NEDD4 can degrade ATP citrate lyase (ACLY) through K48-linked ubiquitination, which in turn inhibits lung cancer cell proliferation [ 34 ]. NEDD4 also ubiquitinates and induces degradation of phosphorylated 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL), which will result in the promotion of proliferation and tumorigenesis in NSCLC [ 35 ]. HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1 (HUWE1) can decrease the stability of PCF11 cleavage and polyadenylation factor subunit (PCF11) by ubiquitination, which promotes the proliferation of LUSC cells [ 36 ].…”