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EGFR-vIII downregulated H2AZK4/7AC though the PI3K/AKT-HDAC2 axis to regulate cell cycle progression
Hongyu Zhao1, Yunfei Wang2, Chao Yang2
1Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Background:
The EGFR-vIII mutation is the most common malignant event in GBM. Epigenetic reprogramming in EGFR-activated GBM has recently been suggested to downregulate the expression of tumour suppressor genes. Histone acetylation is important for chromatin structure and function. However, the role and biological function of H2AZK4/7AC in tumours have not yet been clarified.
Results:
In our study, we found that EGFR-vIII negatively regulated H2AZK4/7AC expression though the PI3K/AKT-HDAC2 axis. Because HDAC1 and HDAC2 are highly homologous enzymes that usually form multi-protein complexes for transcriptional regulation and epigenetic landscaping, we simultaneously knocked out HDAC1 and HDAC2 and found that H2AZK4/7AC and H3K27AC were upregulated, which partially released EGFR-vIII-mediated inhibition of USP11, negative regulator of cell cycle. In addition, we demonstrated in vitro and in vivo that FK228 induced G1/S transition arrest in GBM with EGFR-vIII mutation. FK228 could enhance anti-tumour activity by upregulating expression of the tumour suppressor USP11 in GBM cells.
Conclusions:
EGFR-vIII mutation downregulates H2AZK4/7AC and H3K27AC, inhibiting USP11 expression though the PI3K/AKT-HDAC1/2 axis. FK228 is an effective and promising treatment for GBM with EGFR-vIII mutation.
Insights
EGFR-vIII mutation in glioblastoma downregulates tumor suppressor USP11 via epigenetic changes. FK228 drug reverses this, offering a promising treatment by restoring USP11 expression and inhibiting cancer cell growth.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- The Epidermal Growth Factor Receptor variant III (EGFR-vIII) mutation is a key driver in Glioblastoma Multiforme (GBM).
- EGFR activation in GBM is linked to epigenetic reprogramming, potentially silencing tumor suppressor genes.
- The specific role of histone H2AZK4/7AC in tumor biology remains largely uncharacterized.
Purpose of the Study:
- To investigate the regulatory mechanism of H2AZK4/7AC expression in EGFR-vIII mutated GBM.
- To explore the therapeutic potential of FK228 in GBM with EGFR-vIII mutation.
Main Methods:
- Investigated the PI3K/AKT-HDAC2 signaling pathway's role in regulating H2AZK4/7AC.
- Performed simultaneous knockout of HDAC1 and HDAC2 to assess effects on H2AZK4/7AC, H3K27AC, and USP11 expression.
- Evaluated the in vitro and in vivo effects of FK228 on GBM cell cycle progression and tumor suppressor gene expression.
Main Results:
- EGFR-vIII was found to negatively regulate H2AZK4/7AC expression through the PI3K/AKT-HDAC2 axis.
- Knocking out HDAC1 and HDAC2 led to increased H2AZK4/7AC and H3K27AC, partially alleviating EGFR-vIII's inhibition of USP11.
- FK228 treatment induced G1/S cell cycle arrest in EGFR-vIII mutated GBM and upregulated the tumor suppressor USP11.
Conclusions:
- EGFR-vIII mutation downregulates H2AZK4/7AC and H3K27AC, thereby inhibiting USP11 expression via the PI3K/AKT-HDAC1/2 pathway.
- FK228 demonstrates efficacy as a treatment for GBM harboring the EGFR-vIII mutation by enhancing anti-tumor activity through USP11 upregulation.
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