Targeting the SOX2/CDP protein complex with a peptide suppresses the malignant progression of esophageal squamous...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• SOX2 is an oncogene in esophageal squamous cell carcinoma (ESCC).
• Directly targeting SOX2 is challenging due to its essential roles in normal tissue maintenance.
• A novel therapeutic strategy is needed to target ESCC by indirectly inhibiting SOX2 activity.

Purpose of the Study:

• To identify SOX2 binding partners in ESCC.
• To develop a peptide aptamer that disrupts the SOX2 interaction with its binding partner.
• To evaluate the therapeutic potential of this peptide aptamer in inhibiting ESCC progression.

Main Methods:

• Identified CDP as a SOX2 binding partner using Duolink proximity ligation assay, bimolecular fluorescence complementation (BiFc), and immunoprecipitation.
• Screened a peptide aptamer library to find inhibitors of the CDP/SOX2 interaction.
• Tested the efficacy of peptide P58 in vitro and in vivo models of ESCC, including mice and zebrafish.

Main Results:

• CDP (Homeobox protein cut-like 1 or CASP) was identified as a unique SOX2 binding partner enriched in ESCC.
• Peptide aptamer P58 was identified, which effectively blocked the CDP/SOX2 interaction.
• Administration of P58 inhibited ESCC growth, progression, and metastasis in preclinical models.

Conclusions:

• Targeting the SOX2 binding partner CDP with peptide P58 offers a novel therapeutic strategy for ESCC.
• This approach provides an alternative to directly targeting SOX2, circumventing its essential physiological functions.
• Peptide P58 demonstrates potential as a treatment for ESCC, particularly in cases with elevated SOX2 levels.