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Updated: May 23, 2025

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SQSTM1/p62 as a therapeutic target in cancer

Hyeong-Reh C Kim1,2, Abdo J Najy1, Seongho Kim2,3

  • 1Department of Pathology.

Autophagy Reports
|May 21, 2025
PubMed

Insights

Activating SQSTM1 in head and neck cancer promotes autophagy and forms aggresomes, enhancing cell death when combined with radiation therapy. This offers a new strategy for resistant cancers.

Area of Science:

  • Cellular biology
  • Cancer research
  • Molecular signaling pathways

Background:

  • Cell survival is regulated by complex interactions between endoplasmic reticulum stress, autophagy, and apoptosis.
  • Autophagy mediated by cytoplasmic sequestosome 1 (SQSTM1/p62) is linked to head and neck squamous cell carcinoma (HNSCC) progression and treatment resistance.

Purpose of the Study:

  • To investigate the therapeutic potential of pharmacologically activating SQSTM1 in HNSCC.
  • To explore the combined effects of SQSTM1 activation and radiation therapy on HNSCC cell death.

Main Methods:

  • Utilized synthetic small molecule ligands to activate SQSTM1 and induce autophagic flux.
  • Investigated the formation of ubiquitinated caspase-8 (CASP8) aggresomes.
  • Assessed apoptotic cell death in HNSCC cells treated with SQSTM1 activators and radiation.

Main Results:

  • Pharmacological activation of SQSTM1 enhances autophagic flux.
  • Combination therapy of SQSTM1 activation and radiation induces ubiquitinated CASP8 aggresome formation.
  • This combination leads to apoptotic cell death in HNSCC cells, including those resistant to apoptosis and therapy.

Conclusions:

  • Pharmacological activation of SQSTM1 represents a promising therapeutic strategy for HNSCC.
  • Targeting SQSTM1-mediated autophagy and aggresome formation can overcome apoptosis and therapy resistance in HNSCC.
Keywords:
CASP8 aggresomeER stressSQSTM1/p62apoptosisautophagy/macroautophagysmall molecule ligand

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