FTSJ1 regulates tRNA 2'-O-methyladenosine modification and suppresses the malignancy of NSCLC via inhibiting DRAM1 expression.
A549 Cells
Adenosine
/ analogs & derivatives
Animals
Apoptosis
Carcinoma, Non-Small-Cell Lung
/ enzymology
Cell Movement
Cell Proliferation
Down-Regulation
Female
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms
/ enzymology
Membrane Proteins
/ genetics
Methyltransferases
/ genetics
Mice, Inbred BALB C
Mice, Nude
Neoplasm Invasiveness
Nuclear Proteins
/ genetics
RNA, Transfer
/ genetics
Signal Transduction
Tumor Burden
Tumor Suppressor Proteins
/ genetics
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
11 05 2020
11 05 2020
Historique:
received:
30
01
2020
accepted:
14
04
2020
revised:
14
04
2020
entrez:
13
5
2020
pubmed:
13
5
2020
medline:
10
3
2021
Statut:
epublish
Résumé
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 2'-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.
Identifiants
pubmed: 32393790
doi: 10.1038/s41419-020-2525-x
pii: 10.1038/s41419-020-2525-x
pmc: PMC7214438
doi:
Substances chimiques
DRAM1 protein, human
0
Membrane Proteins
0
Nuclear Proteins
0
Tumor Suppressor Proteins
0
2'-O-methyladenosine
02YX82IHZ5
RNA, Transfer
9014-25-9
FTSJ1 protein, human
EC 2.1.1.-
Methyltransferases
EC 2.1.1.-
Adenosine
K72T3FS567
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
348Commentaires et corrections
Type : ErratumIn
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