Targeting <i>TRMT5</i> suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways.

Qiong Zhao; Luwen Zhang; Qiufen HE; Hui Chang; Zhiqiang Wang; Hongcui Cao; Ying Zhou; Ruolang Pan; Ye Chen

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Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways.

Author: Qiong ZHAO ¹ ; Luwen ZHANG ¹ ; Qiufen HE ¹ ; Hui CHANG ¹ ; Zhiqiang WANG ¹ ; Hongcui CAO ² ; Ying ZHOU ³ ; Ruolang PAN ⁴ ; Ye CHEN ⁵
Author Information

1. Department of Genetics, and Department of Genetic and Metabolic Disease, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
2. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
3. Xiangshan Hospital of TCM Medical and Health Group, Ningbo 315700, China.
4. Zhejiang Provincial Key Laboratory of Cell-Based Drug and Applied Technology Development, Hangzhou 311121, China. yechency@zju.edu.cn, panrl@zju.edu.cn.
5. Department of Genetics, and Department of Genetic and Metabolic Disease, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China. yechency@zju.edu.cn.
Publication Type:Journal Article
Keywords: Hepatocellular carcinoma (HCC); Hypoxia-inducible factor-1α (HIF-1α); Transfer RNA (tRNA); tRNA methyltransferase 5 (TRMT5)
MeSH: Humans; Carcinoma, Hepatocellular/pathology*; Cell Hypoxia; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*; Liver Neoplasms/pathology*; Signal Transduction/genetics*; tRNA Methyltransferases/metabolism*
From: Journal of Zhejiang University. Science. B 2023;24(1):50-63
CountryChina
Language:English
Abstract: Accumulating evidence has confirmed the links between transfer RNA (tRNA) modifications and tumor progression. The present study is the first to explore the role of tRNA methyltransferase 5 (TRMT5), which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma (HCC) progression. Here, based on bioinformatics and clinical analyses, we identified that TRMT5 expression was upregulated in HCC, which correlated with poor prognosis. Silencing TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro, which may be partially explained by declined extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Mechanistically, we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1 (HIF-1) signaling pathway by preventing HIF-1α stability through the enhancement of cellular oxygen content. Moreover, our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-‍1α. In conclusion, our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy drugs. Thus, TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.