FTSJ1 regulates tRNA 2ʹ-O-methyladenosine modification and suppresses the malignancy of NSCLC via inhibiting DRAM1 expression

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. The mechanisms underlying NSCLC tumorigenesis are incompletely understood. Transfer RNA (tRNA) modification is emerging as a novel regulatory mechanism for carcinogenesis. However, the role of tRNA modification in NSCLC remains obscure. In this study, HPLC/MS assay was used to quantify tRNA modification levels in NSCLC tissues and cells. tRNA-modifying enzyme genes were identified by comparative genomics and validated by qRT-PCR analysis. The biological functions of tRNA-modifying gene in NSCLC were investigated in vitro and in vivo. The mechanisms of tRNA-modifying gene in NSCLC were explored by RNA-seq, qRT-PCR, and rescue assays. The results showed that a total of 18 types of tRNA modifications and up to seven tRNA-modifying genes were significantly downregulated in NSCLC tumor tissues compared with that in normal tissues, with the 2ʹ-O-methyladenosine (Am) modification displaying the lowest level in tumor tissues. Loss-and gain-of-function assays revealed that the amount of Am in tRNAs was significantly associated with expression levels of FTSJ1, which was also downregulated in NSCLC tissues and cells. Upregulation of FTSJ1 inhibited proliferation, migration, and promoted apoptosis of NSCLC cells in vitro. Silencing of FTSJ1 resulted in the opposite effects. In vivo assay confirmed that overexpression of FTSJ1 significantly suppressed the growth of NSCLC cells. Mechanistically, overexpression of FTSJ1 led to a decreased expression of DRAM1. Whereas knockdown of FTSJ1 resulted in an increased expression of DRAM1. Furthermore, silencing of DRAM1 substantially augmented the antitumor effect of FTSJ1 on NSCLC cells. Our findings suggested an important mechanism of tRNA modifications in NSCLC and demonstrated novel roles of FTSJ1 as both tRNA Am modifier and tumor suppressor in NSCLC.

The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance

“…Consistently with the well known FTSJ1 implication in ID and more recently in cancer (Holzer et al 2019; Q. He et al 2020), we found 36 differentially expressed miRNAs, most of which were already associated with brain diseases and functioning and/or cancer development. The most prevalent associated cancer types were the ones related to the brain tissues.…”

“…As FTSJ1 mutated LCLs originated from patients affected by NSXLID and regarding the recent link of FTSJ1 implication in cancer control pathways (Holzer et al 2019; Q. He et al 2020) and the cancer related miRNAs deregulated in patients’ LCLs (Figure. 2b), we selected representative and disease-relevant deregulated mRNAs obtained in the RNAseq analysis based on their fold change level of expression and related involvement in brain or cancer diseases.…”

“…SPARC gene product activity was proposed to be involved in both metastasis and tumour suppression (Tai and Tang 2008; Holzer et al 2019; Q. He et al 2020). We also investigated the SPARC mRNA steady state level in control and mutated FTSJ1 LCLs.…”

“…The loss of certain Nm modifications and/or Nm-modifying enzymes has been associated with various pathological conditions (reviewed in (Dimitrova, Teysset, and Carré 2019)), among which cancers (Liu et al 2017; El Hassouni et al 2019; Q. He et al 2020; Marcel et al 2020) and brain diseases (Jia, Mu, and Ackerman 2012; Abe et al 2014; Guy et al 2015; Cavaillé 2017) stand out the most.…”

Roles of tRNA metabolism in aging and lifespan

“…In their metabolic process, defects in any step may cause various human diseases [82][83][84] . For example, the tRNAmodifying enzyme FTSJ1 was down-regulated in nonsmall cell lung cancer (NSCLC) tissues 85 . Importantly, FTSJ1 inhibited the growth of NSCLC cells by reducing the expression of DNA damage-regulated autophagy modulator 1.…”