Targeting c‐Myc transactivation by LMNA inhibits tRNA processing essential for malate‐aspartate shuttle and tumour progression

Abstract

Background

A series of studies have demonstrated the emerging involvement of transfer RNA (tRNA) processing during the progression of tumours. Nevertheless, the roles and regulating mechanisms of tRNA processing genes in neuroblastoma (NB), the prevalent malignant tumour outside the brain in children, are yet unknown.

Methods

Analysis of multi‐omics results was conducted to identify crucial regulators of downstream tRNA processing genes. Co‐immunoprecipitation and mass spectrometry methods were utilised to measure interaction between proteins. The impact of transcriptional regulators on expression of downstream genes was measured by dual‐luciferase reporter, chromatin immunoprecipitation, western blotting and real‐time quantitative reverse transcription‐polymerase chain reaction (RT‐PCR) methods. Studies have been conducted to reveal impact and mechanisms of transcriptional regulators on biological processes of NB. Survival differences were analysed using the log‐rank test.

Results

c‐Myc was identified as a transcription factor driving tRNA processing gene expression and subsequent malate‐aspartate shuttle (MAS) in NB cells. Mechanistically, c‐Myc directly promoted the expression of glutamyl‐prolyl‐tRNA synthetase ( EPRS) and leucyl‐tRNA synthetase ( LARS), resulting in translational up‐regulation of glutamic‐oxaloacetic transaminase 1 (GOT1) as well as malate dehydrogenase 1 (MDH1) via inhibiting general control nonrepressed 2 or activating mechanistic target of rapamycin signalling. Meanwhile, lamin A (LMNA) inhibited c‐Myc transactivation via physical interaction, leading to suppression of MAS, aerobic glycolysis, tumourigenesis and aggressiveness. Pre‐clinically, lobeline was discovered as a LMNA‐binding compound to facilitate its interaction with c‐Myc, which inhibited aminoacyl‐tRNA synthetase expression, MAS and tumour progression of NB, as well as growth of organoid derived from c‐Myc knock‐in mice. Low levels of LMNA or elevated expression of c‐Myc, EPRS, LARS, GOT1 or MDH1 were linked to a worse outcome and a shorter survival time of clinical NB patients.

Conclusions

These results suggest that targeting c‐Myc transactivation by LMNA inhibits tRNA processing essential for MAS and tumour progression.

Abstract

• c‐Myc drives transcription of tRNA processing genes EPRS and LARS essential for tumour progression.

• EPRS and LARS facilitate MAS via translational up‐regulation of GOT1 and MDH1 in NB cells.

• LMNA interacts with and inhibits c‐Myc activity in tRNA processing, MAS and NB progression.

• Therapeutic targeting the LMNA‒c‐Myc interaction by lobeline inhibits tumourigenesis and aggressiveness.