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HECW2 suppresses non-small cell lung cancer progression by destabilizing SCNN1A and inactivating AKT/mTOR pathway

Lan Shao1, Jialong Shen1, Yujing Weng1

  • 1Department of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.

Biochemical Pharmacology
|July 31, 2026
PubMed

Insights

HECT, C2, and WW domain-containing E3 ubiquitin protein ligase 2 (HECW2) is downregulated in non-small cell lung cancer (NSCLC), inhibiting tumor growth. HECW2 inactivation of the AKT/mTOR pathway via SCNN1A ubiquitination presents a potential therapeutic target for NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • HECT, C2, and WW domain-containing E3 ubiquitin protein ligase 2 (HECW2) role in tumors is known, but its function in non-small cell lung cancer (NSCLC) is unclear.
  • Investigating HECW2 in NSCLC is crucial for understanding lung cancer pathogenesis and identifying new therapeutic strategies.

Purpose of the Study:

  • To elucidate the role and underlying mechanisms of HECW2 in NSCLC.
  • To determine the relationship between HECW2, SCNN1A, and the AKT/mTOR pathway in NSCLC progression.

Main Methods:

  • Analysis of NSCLC mRNA profiles from public databases (Gene Expression Omnibus).
  • In vitro and in vivo functional experiments assessing HECW2's effect on NSCLC cell phenotype and tumor growth.
  • Co-Immunoprecipitation, GST pull-down, and Western blot assays to confirm HECW2-SCNN1A interaction and ubiquitination.
  • Pharmacological inhibition of AKT/mTOR pathway (MK2206, SC79) to verify pathway involvement.

Main Results:

  • HECW2 expression is downregulated in NSCLC, correlating with poor prognosis.
  • HECW2 overexpression suppresses NSCLC cell proliferation, migration, and invasion, and inhibits tumor growth in vivo.
  • HECW2 targets SCNN1A for K48-linked ubiquitination and proteasomal degradation, leading to AKT/mTOR pathway inactivation.
  • SCNN1A overexpression or AKT inhibition reverses the anti-tumor effects of HECW2 overexpression.

Conclusions:

  • HECW2 acts as a tumor suppressor in NSCLC by degrading SCNN1A and inactivating the AKT/mTOR pathway.
  • HECW2 represents a potential therapeutic target for NSCLC treatment.
Keywords:
HECW2Lung cancerMigrationProliferationSCNN1AUbiquitination

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