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SHF Acts as a Novel Tumor Suppressor in Glioblastoma Multiforme by Disrupting STAT3 Dimerization
Jingjing Wang1,2, Zixuan Huang1,2, Li Ji1,2
1Department of Laboratory Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, China.
Abstract:
Sustained activation of signal transducer and activator of transcription 3 (STAT3) is a critical contributor in tumorigenesis and chemoresistance, thus making it an attractive cancer therapeutic target. Here, SH2 domain-containing adapter protein F (SHF) is identified as a tumor suppressor in glioblastoma Multiforme (GBM) and its negative regulation of STAT3 activity is characterized. Mechanically, SHF selectively binds and inhibits acetylated STAT3 dimerization without affecting STAT3 phosphorylation or acetylation. Additionally, by blocking STAT3-DNMT1 (DNA Methyltransferase 1) interaction, SHF relieves methylation of tumor suppressor genes. The SH2 domain is documented to be essential for SHF's actions on STAT3, and almost entirely replaces the functions of SHF on STAT3 independently. Moreover, the peptide C16 a peptide derived from the STAT3-binding sites of SHF inhibits STAT3 dimerization and STAT3/DNMT1 interaction, and achieves remarkable growth inhibition in GBM cells in vitro and in vivo. These findings strongly identify targeting of the SHF/STAT3 interaction as a promising strategy for developing an optimal STAT3 inhibitor and provide early evidence of the potential clinical efficacy of STAT3 inhibitors such as C16 in GBM.
Insights
SH2 domain-containing adapter protein F (SHF) acts as a tumor suppressor in glioblastoma by inhibiting signal transducer and activator of transcription 3 (STAT3) dimerization. Targeting the SHF/STAT3 interaction with peptides like C16 shows promise for GBM therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Sustained activation of signal transducer and activator of transcription 3 (STAT3) promotes tumorigenesis and chemoresistance.
- STAT3 is a key target for cancer therapeutics.
Purpose of the Study:
- To identify and characterize novel tumor suppressors targeting STAT3 in glioblastoma.
- To elucidate the mechanism by which SH2 domain-containing adapter protein F (SHF) regulates STAT3 activity.
Main Methods:
- Characterization of SHF's interaction with STAT3.
- Assessment of SHF's effect on STAT3 dimerization and DNA Methyltransferase 1 (DNMT1) interaction.
- In vitro and in vivo evaluation of peptide C16 efficacy in glioblastoma models.
Main Results:
- SHF selectively inhibits acetylated STAT3 dimerization without affecting phosphorylation or acetylation.
- SHF blocks STAT3-DNMT1 interaction, reducing tumor suppressor gene methylation.
- The SH2 domain of SHF is critical for its inhibitory function on STAT3.
- Peptide C16, derived from SHF, inhibits STAT3 dimerization and STAT3/DNMT1 interaction, significantly reducing GBM cell growth.
Conclusions:
- SHF functions as a tumor suppressor in glioblastoma by negatively regulating STAT3.
- Targeting the SHF/STAT3 interaction is a viable strategy for developing novel STAT3 inhibitors.
- The peptide C16 demonstrates potential clinical efficacy for glioblastoma treatment.
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