GSK3β as a potential regulator in AML: A pan-cancer multi-omics analysis

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• The specific functions of glycogen synthase kinase 3 alpha (GSK3α) and glycogen synthase kinase 3 beta (GSK3β) in cancer development and immune response are not well understood.
• Glycogen synthase kinase 3 (GSK3) isoforms play critical roles in various cellular processes, including tumorigenesis and immune modulation, but their isoform-specific contributions across different malignancies require further elucidation.

Purpose of the Study:

• To comprehensively analyze the expression patterns and functional significance of GSK3α and GSK3β across a wide range of cancers using integrated multi-omics data.
• To evaluate the potential of GSK3 isoforms as diagnostic biomarkers and prognostic indicators in various malignancies, with a focus on acute myeloid leukemia (AML).
• To investigate the impact of GSK3 isoforms on the tumor microenvironment (TME) and validate the therapeutic potential of GSK3 inhibition in AML.

Main Methods:

• Integration of multi-omics data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and single-cell RNA sequencing datasets for 31 cancer types.
• Functional clustering, survival analysis using Cox regression, and immune infiltration analysis to assess the roles of GSK3α and GSK3β.
• In vitro validation using AML cell lines treated with the GSK3 inhibitor CHIR-99021 to assess effects on proliferation, apoptosis, cell cycle, and c-Myc expression.

Main Results:

• Divergent dysregulation of GSK3 isoforms was observed across 31 malignancies: GSK3α was upregulated in 19 solid tumors but suppressed in AML, while GSK3β was elevated in 23 cancers and high-risk AML subtypes.
• GSK3β demonstrated superior diagnostic performance as a pan-cancer biomarker compared to GSK3α. High GSK3α expression predicted poor overall survival (OS) in adrenocortical carcinoma (ACC) and mesothelioma (MESO), while GSK3β independently stratified cytogenetic-risk AML.
• Isoform-specific modulation of the tumor microenvironment (TME) was identified: GSK3α correlated with protumorigenic immune cells (Treg/Th17), whereas GSK3β showed negative associations with cytotoxic effectors. Inhibition of GSK3 in AML cells suppressed proliferation, induced apoptosis, and caused cell cycle arrest.

Conclusions:

• GSK3β is identified as a key regulator of oncogenic programs in AML and a promising therapeutic target.
• This study provides a comprehensive pan-cancer atlas of GSK3 isoform-specific functions, highlighting their distinct roles in tumorigenesis and immune modulation.
• GSK3β emerges as a high-priority therapeutic target due to its significant role in AML pathogenesis and its potential as a pan-cancer biomarker.