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

Zhang, Mingpeng; Kan, Duo; Zhang, Boya; Chen, Xueqiao; Wang, Chun; Chen, Songmao; Gao, Wenlong; Yang, Zhao; Li, Yang; Chen, Yutong; Zhu, Shimiao; Wen, Simeng; Niu, Yuanjie; Shang, Zhiqun

doi:10.1186/s13046-023-02777-z

Cited by 12 publications

(1 citation statement)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S8A ). It has been documented that SP1 could regulate METTL1 expression in cancer cells 84 . Hence, there is a question regarding whether SP1 also regulates the expression of METTL1 during senescence.…”

Section: Resultsmentioning

confidence: 99%

Perturbation of METTL1-mediated tRNA N7- methylguanosine modification induces senescence and aging

Fu,

Jiang,

Zhang

et al. 2024

Nat Commun

View full text Add to dashboard Cite

Cellular senescence is characterized by a decrease in protein synthesis, although the underlying processes are mostly unclear. Chemical modifications to transfer RNAs (tRNAs) frequently influence tRNA activity, which is crucial for translation. We describe how tRNA N7-methylguanosine (m7G46) methylation, catalyzed by METTL1-WDR4, regulates translation and influences senescence phenotypes. Mettl1/Wdr4 and m7G gradually diminish with senescence and aging. A decrease in METTL1 causes a reduction in tRNAs, especially those with the m7G modification, via the rapid tRNA degradation (RTD) pathway. The decreases cause ribosomes to stall at certain codons, impeding the translation of mRNA that is essential in pathways such as Wnt signaling and ribosome biogenesis. Furthermore, chronic ribosome stalling stimulates the ribotoxic and integrative stress responses, which induce senescence-associated secretory phenotype. Moreover, restoring eEF1A protein mitigates senescence phenotypes caused by METTL1 deficiency by reducing RTD. Our findings demonstrate that tRNA m7G modification is essential for preventing premature senescence and aging by enabling efficient mRNA translation.

show abstract

Section: Resultsmentioning

confidence: 99%

Perturbation of METTL1-mediated tRNA N7- methylguanosine modification induces senescence and aging

Fu,

Jiang,

Zhang

et al. 2024

Nat Commun

View full text Add to dashboard Cite

show abstract

The m7G Methyltransferase Mettl1 Drives Cardiac Hypertrophy by Regulating SRSF9‐Mediated Splicing of NFATc4

Yu,

Sun,

et al. 2024

Advanced Science

View full text Add to dashboard Cite

Cardiac hypertrophy is a key factor driving heart failure (HF), yet its pathogenesis remains incompletely elucidated. Mettl1‐catalyzed RNA N7‐methylguanosine (m7G) modification has been implicated in ischemic cardiac injury and fibrosis. This study aims to elucidate the role of Mettl1 and the mechanism underlying non‐ischemic cardiac hypertrophy and HF. It is found that Mettl1 is upregulated in human failing hearts and hypertrophic murine hearts following transverse aortic constriction (TAC) and Angiotensin II (Ang II) infusion. YY1 acts as a transcriptional factor for Mettl1 during cardiac hypertrophy. Mettl1 knockout alleviates cardiac hypertrophy and dysfunction upon pressure overload from TAC or Ang II stimulation. Conversely, cardiac‐specific overexpression of Mettl1 results in cardiac remodeling. Mechanically, Mettl1 increases SRSF9 expression by inducing m7G modification of SRSF9 mRNA, facilitating alternative splicing and stabilization of NFATc4, thereby promoting cardiac hypertrophy. Moreover, the knockdown of SRSF9 protects against TAC‐ or Mettl1‐induced cardiac hypertrophic phenotypes in vivo and in vitro. The study identifies Mettl1 as a crucial regulator of cardiac hypertrophy, providing a novel therapeutic target for HF.

show abstract

RNA Methyltransferase NSUN5 Promotes Esophageal Cancer via 5‐Methylcytosine Modification of METTL1

Cui,

Hu,

Zhang

2024

Molecular Carcinogenesis

View full text Add to dashboard Cite

Aberrant RNA modifications can drive carcinogenic transformation and tumor progression, with 5‐methylcytosine (m5C) emerging as one of the predominant RNA modifications in eukaryotic cells. However, the function and molecular mechanisms of m5C in esophageal cancer (ESCA) remain insufficiently defined. Here we report that the m5C methyltransferase NOP2/Sun domain family member 5 (NSUN5) is significantly upregulated in ESCA tumors and shows promising diagnostic potential. Functionally, knockdown of NSUN5 impairs the proliferation capacity of ESCA cells and arrests cell cycle at the G0/G1 phase, while enforced expression of NSUN5 accelerates ESCA progression. In vivo, deficiency of NSUN5 significantly reduces tumor growth in a cell‐based xenograft mouse model. Mechanistically, NSUN5 correlates with the oncogenic methyltransferase like 1 (METTL1), positively regulating its expression; NSUN5 binds directly to the METTL1 transcript, facilitating its m5C modification in ESCA cells. Additionally, overexpression of METTL1 effectively counteracts the tumor‐suppressive effects resulting from NSUN5 ablation in both in vitro and in vivo settings. A comprehensive pan‐cancer analysis further underscores NSUN5's essential role in digestive system tumors, with downregulation of NSUN5 notably inhibiting gastric and colon cancer cell growth. These findings provide new insights into epigenetic regulation in ESCA and propose the NSUN5/METTL1 axis as a promising therapeutic target for this malignancy.

show abstract

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

Cited by 12 publications

References 34 publications

Perturbation of METTL1-mediated tRNA N7- methylguanosine modification induces senescence and aging

Perturbation of METTL1-mediated tRNA N7- methylguanosine modification induces senescence and aging

The m7G Methyltransferase Mettl1 Drives Cardiac Hypertrophy by Regulating SRSF9‐Mediated Splicing of NFATc4

RNA Methyltransferase NSUN5 Promotes Esophageal Cancer via 5‐Methylcytosine Modification of METTL1

Contact Info

Product

Resources

About