Gliomas are the most common primary intracranial
tumor, accounting for more than 70% of brain
malignancies. Studies indicate that highly upregulated in
liver cancer (HULC), a
long noncoding RNA (
lncRNA), functions as an oncogene in
gliomas. However, the underlying mechanism of HULC in
gliomas remains under-studied and was subsequently investigated in the current study. Brain tissues were clinically collected from 50 patients with
glioblastoma (GBM) and 35 patients with acute
craniocerebral injury, followed by immunohistochemical detection of the expression patterns of Forkhead box M1 (FOXM1), anterior gradient 2 (AGR2), and
hypoxia-inducible factor-1α (HIF-1α). After flow cytometry-based sorting of the CD133+
glioma stem cells (GSCs) from the U251 cell line, the obtained cells were subjected to
lentivirus infection. Afterwards, the proliferation, stemness, and apoptosis of GSCs were evaluated using sphere formation, immunofluorescence, and flow cytometry assays, respectively. In addition, the interactions among HULC, FOXM1, AGR2, and HIF-1α were identified using
RNA immunoprecipitation (RIP),
RNA pull-down,
Chromatin immunoprecipitation (ChIP), IP, and dual
luciferase reporter assays. Last, the specific effects were validated in vivo. HULC was upregulated in GBM tissues and GSCs, which may promote the progression of
glioma. On the other hand, silencing of HULC reduced the stemness, inhibited the proliferation, and promoted the apoptosis and differentiation of GSCs. In addition, HULC further stabilized FOXM1 expression in GSCs through ubiquitination, while FOXM1 activated AGR2 transcription to promote HIF-1α expression. Moreover, HULC promoted the glycolysis and stemness of GSCs through its regulation of the FOXM1/AGR2/HIF-1α axis, consequently exacerbating the occurrence and development of
glioma. The findings obtained in our study indicate that HULC stabilizes the
FOXM1 protein by ubiquitination to upregulate the expression of AGR2 and HIF-1α, which further promote the glycolysis of and maintain the stemness of GSCs, to enhance the tumorigenicity of GSCs, highlighting a novel therapeutic target for
glioma.