PDGF signaling inhibits mitophagy in glioblastoma stem cells through N6-methyladenosine

被引：53

作者：

Lv, Deguan ^{[1
,2
]}

Gimple, Ryan C. ^{[2
,3
]}

Zhong, Cuiqing ^{[1
,4
]}

Wu, Qiulian ^{[1
]}

Yang, Kailin ^{[5
]}

Prager, Briana C. ^{[2
,6
]}

Godugu, Bhaskar ^{[7
]}

Qiu, Zhixin ^{[1
,2
]}

Zhao, Linjie ^{[1
,2
]}

Zhang, Guoxin ^{[2
]}

Dixit, Deobrat ^{[2
]}

Lee, Derrick ^{[1
,2
]}

Shen, Jia Z. ^{[8
]}

Li, Xiqing ^{[2
,9
]}

Xie, Qi ^{[2
,10
]}

Wang, Xiuxing ^{[2
,11
]}

Agnihotri, Sameer ^{[12
]}

Rich, Jeremy N. ^{[1
,2
,13
]}

机构：

[1] Univ Pittsburgh, Hillman Canc Ctr, Med Ctr, Pittsburgh, PA 15232 USA

[2] Univ Calif San Diego, Sch Med, Div Regenerat Med, San Diego, CA 92037 USA

[3] Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA

[4] Salk Inst Biol Studies, Gene Express Lab, San Diego, CA 92037 USA

[5] Cleveland Clin, Dept Radiat Oncol, Taussig Canc Ctr, Cleveland, OH 44195 USA

[6] Case Western Reserve Univ, Cleveland Clin Lerner Coll Med, Cleveland, OH 44195 USA

[7] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA

[8] Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, NCI Designated Canc Ctr, San Diego, CA 92037 USA

[9] Zhengzhou Univ Peoples Hosp, Henan Prov Peoples Hosp, Dept Oncol, Zhengzhou 450003, Henan, Peoples R China

[10] Westlake Univ, Westlake Inst Adv Study, Inst Basic Med Sci, Hangzhou 310024, Zhejiang, Peoples R China

[11] Nanjing Med Univ, Sch Basic Med Sci, Nanjing 211166, Jiangsu, Peoples R China

[12] UPMC Childrens Hosp Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15224 USA

[13] Univ Pittsburgh, Dept Neurol, Sch Med, Pittsburgh, PA 15232 USA

来源：

DEVELOPMENTAL CELL | 2022年 / 57卷 / 12期

关键词：

MESSENGER-RNA; M(6)A MODIFICATION; SELF-RENEWAL; EXPRESSION; GROWTH; METHYLATION; TBK1; PROLIFERATION; RECRUITMENT; ACTIVATION;

D O I：

10.1016/j.devcel.2022.05.007

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Dysregulated growth factor receptor pathways, RNA modifications, and metabolism each promote tumor heterogeneity. Here, we demonstrate that platelet-derived growth factor (PDGF) signaling induces N-6-meth-yladenosine (m(6)A) accumulation in glioblastoma (GBM) stem cells (GSCs) to regulate mitophagy. PDGF ligands stimulate early growth response 1 (EGR1) transcription to induce methyltransferase-like 3 (METTL3) to promote GSC proliferation and self-renewal. Targeting the PDGF-METTL3 axis inhibits mitophagy by regulating m(6)A modification of optineurin (OPTN). Forced OPTN expression phenocopies PDGF inhibition, and OPTN levels portend longer survival of GBM patients; these results suggest a tumor-suppressive role for OPTN. Pharmacologic targeting of METTL3 augments anti-tumor efficacy of PDGF receptor (PDGFR) and mitophagy inhibitors in vitro and in vivo. Collectively, we define PDGF signaling as an upstream regulator of oncogenic m(6)A regulation, driving tumor metabolism to promote cancer stem cell maintenance, highlighting PDGF-METTL3-OPTN signaling as a GBM therapeutic target.

引用

页码：1466 / +

页数：23

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