Upregulation of HAS2 promotes glioma cell proliferation and chemoresistance via c-myc

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant human brain tumor. Although comprehensive therapies, including chemotherapy and radiotherapy following surgery, have shown promise in prolonging survival, the prognosis for GBM patients remains poor, with an overall survival rate of only 14.6 months. Chemoresistance is a major obstacle to successful treatment and contributes to relapse and poor survival rates in glioma patients. Therefore, there is an urgent need for novel strategies to overcome chemoresistance and improve treatment outcomes for human glioma patients. Recent studies have shown that the tumor microenvironment plays a key role in chemoresistance. Our study demonstrates that upregulation of HAS2 and subsequent hyaluronan secretion promotes glioma cell proliferation, invasion, and chemoresistance in vitro and in vivo through the c-myc pathway. Targeting HAS2 sensitizes glioma cells to chemotherapeutic agents. Additionally, we found that hypoxia-inducible factor HIF1α regulates HAS2 expression. Together, our findings provide insights into the dysregulation of HAS2 and its role in chemoresistance and suggest potential therapeutic strategies for GBM. •Research shows that HAS2, an enzyme synthesizing hyaluronan, is upregulated in glioma cells and tissues, promoting tumor proliferation.•Suppressing HAS2 and inhibiting HA with 4-MU or HYAL sensitizes glioma cells to TMZ, a common first-line chemotherapeutic for glioma.•HAS2 is essential for glioma tumorigenesis, and its inhibition sensitizes glioma to the cytotoxic effects of TMZ in vivo.•HAS2 promotes glioma proliferation via c-Myc activity, which is linked to therapy resistance.•HIF1α, a key regulator of genes in cancer cell hypoxia response, can stimulate HAS2 expression in gliomas.