GINS2 regulates temozolomide chemosensitivity via the EGR1/ECT2 axis in gliomas

Temozolomide (TMZ), a DNA alkylating agent, is the standard treatment for glioma, the most prevalent central nervous system malignancy. While TMZ-based regimens often yield significant clinical responses, some patients experience poor outcomes or disease relapse, likely due to the glioma cells’ robust DNA damage response (DDR) that reduces chemosensitivity. GINS2, a subunit of DNA helicase, plays a crucial role in maintaining genomic stability and is highly expressed in various cancers, where it supports tumor progression. Our study found that GINS2 is upregulated in TMZ-treated glioma cells and co-localizes with γH2AX, indicating its involvement in the TMZ-induced DDR. GINS2 influences the malignant properties and TMZ sensitivity of glioma cells primarily by enhancing DNA damage repair through modulation of mRNA stability of early growth response factor 1 (EGR1), which regulates the transcription of epithelial cell-transforming sequence 2 (ECT2). We developed a GINS2-EGR1-ECT2 prognostic model that accurately predicts patient survival. Additionally, we identified Palbociclib/BIX-02189, which reduces GINS2 expression and works synergistically with TMZ to inhibit glioma cell proliferation. These results reveal a new mechanism by which GINS2 affects BIX 02189 TMZ sensitivity in glioma cells and suggest a promising combination therapy approach for treating glioma.