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HECW2 suppresses non-small cell lung cancer progression by destabilizing SCNN1A and inactivating AKT/mTOR pathway
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DOI：10.1016/j.bcp.2026.118305.png)
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Abstract
En 中文
HECW2 (HECT, C2, and WW domain-containing E3 ubiquitin protein ligase 2, also known as NEDL2) has been implicated in numerous tumors, whereas its effect in non-small cell lung cancer (NSCLC) remains unknown. This study aimed to investigate the role of HECW2 in NSCLC and its underlying mechanisms. The mRNA profiles GSE27262, GSE43458, GSE19804, and GSE19188 were collected from the Gene Expression Omnibus database, and the E3 ubiquitin ligases were obtained from the Ubibrowse database. Moreover, we investigated the expressions and clinical prognosis of HECW2 using the online databases. To assess the effect of HECW2 on the phenotype of NSCLC, we performed both in vitro and in vivo functional experiments. Co-Immunoprecipitation, GST pull-down, and Western blot assays were used to verify the regulation of SCNN1A by HECW2. The relationship between SCNN1A and AKT/mTOR pathway was further verified using MK2206 and SC79. HECW2 was downregulated in NSCLC and the HECW2-low expression was associated with the poor prognosis of lung cancer. HECW2 overexpression inhibited cell proliferation, migration, and invasion in H1975 cells and restricted tumor growth in tumor-bearing mice, whereas an opposite effect was observed in the HECW2-knockdown PC9 cells. SCNN1A overexpression and AKT inhibition reversed the inhibiting proliferation and migration abilities of HECW2 overexpression and the promotion effect of SCNN1A overexpression, respectively. HECW2 binds to SCNN1A and promoted SCNN1A ubiquitination with the K48-linked manner and proteasomal degradation. In conclusion, HECW2 inhibited the development of NSCLC via mediating SCNN1A ubiquitination by inactivating the AKT/mTOR pathway and could be a potential target in NSCLC.
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