P300/SP1 complex mediating elevated METTL1 regulates CDK14 mRNA stability via internal m7G modification in CRPC

Journal of Experimental & Clinical Cancer Research

Research

Boya Zhang¹  Xueqiao Chen²  Simeng Wen²  Duo Kan²  Chun Wang²  Yutong Chen²  Zhao Yang²  Yuanjie Niu²  Mingpeng Zhang²  Songmao Chen²  Wenlong Gao²  Yang Li²  Shimiao Zhu²  Zhiqun Shang² 

[1] Bone and Soft Tissue Department, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 450000, Zhengzhou, China;Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, 300211, Tianjin, China;

关键词: METTL1;    m7G;    P300/SP1 complex;    CDK14;    CRPC;   

DOI  :  10.1186/s13046-023-02777-z

 received in 2023-04-20, accepted in 2023-07-24,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundN7-methylguanosine (m7G) modification is, a more common epigenetic modification in addition to m6A modification, mainly found in mRNA capsids, mRNA interiors, transfer RNA (tRNA), pri-miRNA, and ribosomal RNA (rRNA). It has been found that m7G modifications play an important role in mRNA transcription, tRNA stability, rRNA processing maturation, and miRNA biosynthesis. However, the role of m7G modifications within mRNA and its “writer” methyltransferase 1(METTL1) in tumors, particularly prostate cancer (PCa), has not been revealed.MethodsThe differential expression level of METTL1 between hormone-sensitive prostate cancer (HSPC) and castrate-resistant prostate cancer (CRPC) was evaluated via RNA-seq and in vitro experiments. The effects of METTL1 on CRPC progression were investigated through in vitro and in vivo assays. The upstream molecular mechanism of METTL1 expression upregulation and the downstream mechanism of its action were explored via Chromatin Immunoprecipitation quantitative reverse transcription polymerase chain reaction (CHIP-qPCR), Co-immunoprecipitation (Co-IP), luciferase reporter assay, transcriptome-sequencing, m7G AlkAniline-Seq, and mRNA degradation experiments, etc.Results and conclusionHere, we found that METTL1 was elevated in CRPC and that patients with METTL1 elevation tended to have a poor prognosis. Functionally, the knockdown of METTL1 in CRPC cells significantly limited cell proliferation and invasive capacity. Mechanistically, we unveiled that P300 can form a complex with SP1 and bind to the promoter region of the METTL1 gene via SP1, thereby mediating METTL1 transcriptional upregulation in CRPC. Subsequently, our findings indicated that METTL1 leads to enhanced mRNA stability of CDK14 by adding m7G modifications inside its mRNA, ultimately promoting CRPC progression.

【 授权许可】

CC BY   
© Italian National Cancer Institute ‘Regina Elena’ 2023

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