2. Academic Validation
  3. Par6/SOX2 interact to modulate stemness maintenance in glioma by regulating the EGFR/PI3K/AKT signaling cascade

Par6/SOX2 interact to modulate stemness maintenance in glioma by regulating the EGFR/PI3K/AKT signaling cascade

  • Oncogene. 2025 Oct 11. doi: 10.1038/s41388-025-03595-7.
Ting Yang # 1,  Yan Zeng # 1,  Ya Li # 1 2,  Yishan Huang 1,  Xin Meng 1,  Chunjiao Lu 1,  Chenchen Zhu 1,  Pei Liu 1,  Jing Liu 3,  Shaocai Hao 4,  Juanjuan Luo 5,  Wei Cui 6,  Xiaojun Yang 7 8 9
Affiliations

Affiliations

  • 1 Neuroscience Center, Shantou University Medical College, Shantou, China.
  • 2 The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 3 The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, China.
  • 4 The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China.
  • 5 Neuroscience Center, Shantou University Medical College, Shantou, China. 15jjluo1@stu.edu.cn.
  • 6 College of Life Science and Biopharmaceutical of Shenyang Pharmaceutical University, Shenyang, China. cuiwei@syphu.edu.cn.
  • 7 The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China. yangx@gdmu.edu.cn.
  • 8 School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China. yangx@gdmu.edu.cn.
  • 9 Engineering Research Center of Key Technique for Biotherapy of Guangdong Province, Shantou University Medical College, Shantou, China. yangx@gdmu.edu.cn.
  • # Contributed equally.
PMID: 41076461 DOI: 10.1038/s41388-025-03595-7
Abstract

Glioma stem cells (GSCs) are a primary factor contributing to the failure of glioma treatment and lead to a poor prognosis for patients with glioma. However, the biological functions and mechanisms involved in regulating stemness maintenance in GSCs are not well understood. Here, we investigated the potential regulatory effects of Par6 on stemness maintenance in GSCs. Our data revealed high expression of Par6 in glioma specimens is usually accompanied by a poor prognosis. Further study indicated Par6 expression might be involved in stemness maintenance of GSCs by directly binding to SOX2 in glioma cells. In contrast, the blockade of Par6/SOX2 interaction with a specific inhibitory peptide (Par6i-P1) significantly suppressed the stemness maintenance of GSCs. Gene manipulation results showed the combination of Par6 and SOX2 promoted stemness maintenance in a complementary manner. Mechanistically, we identified PI3K/Akt signaling pathway as a downstream target of EGFR, which is also transcriptionally regulated by SOX2 in glioma cells. Moreover, a clinical study indicated the coexpression of Par6 and SOX2 predicted poor outcomes for glioma patients, suggesting the Par6/SOX2 interaction might trigger the regulation of stemness maintenance through activating EGFR/PI3K/Akt signaling pathway in glioma. Furthermore, comparing with the scrambled peptide control, the tumorigenicity assay and immunohistochemistry indicated that targeting the Par6/SOX2 interaction might effectively mitigate GSC-mediated chemotherapy resistance in temozolomide (TMZ) treatment, and improve the malignancy and prognosis in mice orthotopically transplanted with GBM. Together, these findings reveal a novel mechanism by which the Par6/SOX2 interaction contributes to the maintenance of stemness in GSCs and may serve as a promising therapeutic target for improving the prognosis of glioma patients.

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