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USP15 negatively regulates lung cancer progression through the TRAF6-BECN1 signaling axis for autophagy induction

Mi-Jeong Kim1, Yoon Min1, Soo-Kyung Jeong2

  • 1Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.

Cell Death & Disease
|April 15, 2022
PubMed

Insights

Ubiquitin-specific peptidase 15 (USP15) inhibits lung cancer progression by deubiquitinating BECN1, thereby attenuating toll-like receptor 4 (TLR4)-induced autophagy. USP15 downregulation promotes cancer cell migration and invasion.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • The TNF receptor-associated factor 6 (TRAF6)-BECN1 signaling axis is crucial for autophagy induction, promoting lung cancer migration and invasion via BECN1 ubiquitination upon toll-like receptor 4 (TLR4) stimulation.
  • Ubiquitin-specific peptidase 15 (USP15) expression is significantly downregulated in non-small cell lung cancer (NSCLC) patients, suggesting a potential role in tumor progression.

Purpose of the Study:

  • To elucidate the molecular and cellular mechanisms by which USP15 negatively regulates lung cancer progression.
  • To investigate the interaction between USP15, BECN1, and TRAF6 in the context of TLR4-induced autophagy and lung cancer cell behavior.

Main Methods:

  • Utilized CRISPR-Cas9 gene-editing to generate USP15-knockout (USP15KO) lung cancer cell lines (A549 and H1299).
  • Performed biochemical studies to analyze USP15-BECN1 interactions and BECN1 deubiquitination.
  • Analyzed clinical data from TCGA and primary NSCLC patients to correlate USP15 expression with cancer progression markers.

Main Results:

  • USP15KO lung cancer cells exhibited increased migration and invasion, with enhanced autophagy induction in response to TLR4 stimulation.
  • USP15 directly interacted with BECN1, inducing its deubiquitination and consequently attenuating autophagy.
  • Low USP15 expression in NSCLC patients correlated with upregulation of pro-cancer genes and downregulation of tumor suppressor genes.

Conclusions:

  • USP15 negatively regulates the TRAF6-BECN1 signaling axis by deubiquitinating BECN1, thereby inhibiting autophagy induction and suppressing lung cancer progression.
  • USP15 acts as a tumor suppressor in NSCLC, and its downregulation is implicated in increased cancer cell migration, invasion, and overall progression.

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