FOSL1 Promotes Proneural-to-mesenchymal Transition of Glioblastoma Stem Cells Via UBC9/CYLD/NF-κB Axis

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2022 Mar 30

PMID 35351656

Authors

Zhengxin Chen

Shuai Wang

Hai-Lin Li

Hui Luo

Xiaoting Wu

Jiacheng Lu

Hong-Wei Wang

Yuanyuan Chen

Dan Chen

Wen-Ting Wu

Shuyu Zhang

Qiongqiong He

Daru Lu

Ning Liu

Yongping You

Wei Wu

Huibo Wang

Affiliations

Soon will be listed here.

Abstract

Proneural (PN) to mesenchymal (MES) transition (PMT) is a crucial phenotypic shift in glioblastoma stem cells (GSCs). However, the mechanisms driving this process remain poorly understood. Here, we report that Fos-like antigen 1 (FOSL1), a component of AP1 transcription factor complexes, is a key player in regulating PMT. FOSL1 is predominantly expressed in the MES subtype, but not PN subtype, of GSCs. Knocking down FOSL1 expression in MES GSCs leads to the loss of MES features and tumor-initiating ability, whereas ectopic expression of FOSL1 in PN GSCs is able to induce PMT and maintain MES features. Moreover, FOSL1 facilitates ionizing radiation (IR)-induced PMT and radioresistance of PN GSCs. Inhibition of FOSL1 enhances the anti-tumor effects of IR by preventing IR-induced PMT. Mechanistically, we find that FOSL1 promotes UBC9-dependent CYLD SUMOylation, thereby inducing K63-linked polyubiquitination of major nuclear factor κB (NF-κB) intermediaries and subsequent NF-κB activation, which results in PMT induction in GSCs. Our study underscores the importance of FOSL1 in the regulation of PMT and suggests that therapeutic targeting of FOSL1 holds promise to attenuate molecular subtype switching in patients with glioblastomas.

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References

Bakiri L, Macho-Maschler S, Custic I, Niemiec J, Guio-Carrion A, Hasenfuss S . Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression. Cell Death Differ. 2014; 22(2):336-50. PMC: 4291495. DOI: 10.1038/cdd.2014.157. View

Minata M, Audia A, Shi J, Lu S, Bernstock J, Pavlyukov M . Phenotypic Plasticity of Invasive Edge Glioma Stem-like Cells in Response to Ionizing Radiation. Cell Rep. 2019; 26(7):1893-1905.e7. PMC: 6594377. DOI: 10.1016/j.celrep.2019.01.076. View

Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L . Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell. 2017; 32(1):42-56.e6. PMC: 5599156. DOI: 10.1016/j.ccell.2017.06.003. View

Masoumi K, Marfany G, Wu Y, Massoumi R . Putative role of SUMOylation in controlling the activity of deubiquitinating enzymes in cancer. Future Oncol. 2016; 12(4):565-74. DOI: 10.2217/fon.15.320. View

Maurus K, Hufnagel A, Geiger F, Graf S, Berking C, Heinemann A . The AP-1 transcription factor FOSL1 causes melanocyte reprogramming and transformation. Oncogene. 2017; 36(36):5110-5121. DOI: 10.1038/onc.2017.135. View

Singh S, Hawkins C, Clarke I, Squire J, Bayani J, Hide T . Identification of human brain tumour initiating cells. Nature. 2004; 432(7015):396-401. DOI: 10.1038/nature03128. View

Cheng P, Wang J, Waghmare I, Sartini S, Coviello V, Zhang Z . FOXD1-ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells. Cancer Res. 2016; 76(24):7219-7230. PMC: 5161538. DOI: 10.1158/0008-5472.CAN-15-2860. View

Phillips H, Kharbanda S, Chen R, Forrest W, Soriano R, Wu T . Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006; 9(3):157-73. DOI: 10.1016/j.ccr.2006.02.019. View

Chen Z, Wang H, Wang S, Fan L, Feng S, Cai X . USP9X deubiquitinates ALDH1A3 and maintains mesenchymal identity in glioblastoma stem cells. J Clin Invest. 2019; 129(5):2043-2055. PMC: 6486342. DOI: 10.1172/JCI126414. View

10.

Harhaj E, Dixit V . Deubiquitinases in the regulation of NF-κB signaling. Cell Res. 2010; 21(1):22-39. PMC: 3075605. DOI: 10.1038/cr.2010.166. View

11.

Moreno M, Pedrosa L, Pare L, Pineda E, Bejarano L, Martinez J . GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma. Cell Rep. 2017; 21(8):2183-2197. DOI: 10.1016/j.celrep.2017.10.083. View

12.

Pecce V, Verrienti A, Fiscon G, Sponziello M, Conte F, Abballe L . The role of FOSL1 in stem-like cell reprogramming processes. Sci Rep. 2021; 11(1):14677. PMC: 8290037. DOI: 10.1038/s41598-021-94072-0. View

13.

Kim S, Ezhilarasan R, Phillips E, Gallego-Perez D, Sparks A, Taylor D . Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner. Cancer Cell. 2016; 29(2):201-13. PMC: 4837946. DOI: 10.1016/j.ccell.2016.01.005. View

14.

Zhang M, Hoyle R, Ma Z, Sun B, Cai W, Cai H . FOSL1 promotes metastasis of head and neck squamous cell carcinoma through super-enhancer-driven transcription program. Mol Ther. 2021; 29(8):2583-2600. PMC: 8353207. DOI: 10.1016/j.ymthe.2021.03.024. View

15.

Peng C, Chen Z, Wang S, Wang H, Qiu W, Zhao L . The Error-Prone DNA Polymerase κ Promotes Temozolomide Resistance in Glioblastoma through Rad17-Dependent Activation of ATR-Chk1 Signaling. Cancer Res. 2016; 76(8):2340-53. DOI: 10.1158/0008-5472.CAN-15-1884. View

16.

Luo H, Chen Z, Wang S, Zhang R, Qiu W, Zhao L . c-Myc-miR-29c-REV3L signalling pathway drives the acquisition of temozolomide resistance in glioblastoma. Brain. 2015; 138(Pt 12):3654-72. DOI: 10.1093/brain/awv287. View

17.

Ozawa T, Riester M, Cheng Y, Huse J, Squatrito M, Helmy K . Most human non-GCIMP glioblastoma subtypes evolve from a common proneural-like precursor glioma. Cancer Cell. 2014; 26(2):288-300. PMC: 4143139. DOI: 10.1016/j.ccr.2014.06.005. View

18.

Verhaak R, Hoadley K, Purdom E, Wang V, Qi Y, Wilkerson M . Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010; 17(1):98-110. PMC: 2818769. DOI: 10.1016/j.ccr.2009.12.020. View

19.

Behnan J, Finocchiaro G, Hanna G . The landscape of the mesenchymal signature in brain tumours. Brain. 2019; 142(4):847-866. PMC: 6485274. DOI: 10.1093/brain/awz044. View

20.

Fedele M, Cerchia L, Pegoraro S, Sgarra R, Manfioletti G . Proneural-Mesenchymal Transition: Phenotypic Plasticity to Acquire Multitherapy Resistance in Glioblastoma. Int J Mol Sci. 2019; 20(11). PMC: 6600373. DOI: 10.3390/ijms20112746. View