VIRMA contributes to non-small cell lung cancer progression via N6-methyladenosine-dependent DAPK3 post-transcriptional modification

Yongfang Xu; Yunhao Chen; Yinan Yao; Haiyang Xie; Guohua Lu; Chengli Du; Jun Cheng; Jianying Zhou

doi:10.1016/j.canlet.2021.08.027

VIRMA contributes to non-small cell lung cancer progression via N⁶-methyladenosine-dependent DAPK3 post-transcriptional modification

Cancer Lett. 2021 Dec 1:522:142-154. doi: 10.1016/j.canlet.2021.08.027. Epub 2021 Sep 11.

Authors

Yongfang Xu¹, Yunhao Chen², Yinan Yao¹, Haiyang Xie², Guohua Lu¹, Chengli Du³, Jun Cheng³, Jianying Zhou⁴

Affiliations

¹ Department of Respiratory Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China.
² Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China.
³ Department of Thoracic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China.
⁴ Department of Respiratory Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China. Electronic address: zjyhz@zju.edu.cn.

PMID: 34520821
DOI: 10.1016/j.canlet.2021.08.027

Abstract

N⁶-methyladenosine (m6A) has been reported to be abnormally expressed in non-small cell lung cancer (NSCLC), and plays a vital role in regulation of cell proliferation, invasion and metastasis. Vir-Like m6A methyltransferase associated (VIRMA, also called KIAA1429) has not been well studied in NSCLC. Thus, in this study, we investigated the biological impact and underlying mechanism of VIRMA in NSCLC. High expression of VIRMA was testified in patients with NSCLC and predicted worse prognosis in patients. VIRMA facilitated cell proliferation and tumor growth both in vitro and in vivo. Furthermore, VIRMA-regulated m6A modifications led to post-transcriptional suppression of death-associated protein kinase 3 (DAPK3, also called ZIP or ZIPK) through the YT521-B homology domain-containing family proteins 2/3(YTHDF2/3). Inhibition of DAPK3 rescued the tumor-suppressive phenotypes induced by VIRMA deficiency. In conclusion, VIRMA-guided m6A modifications promoted NSCLC progression via m6A-dependent degradation of DAPK3 mRNA. Therefore, VIRMA may be a novel therapeutic target in NSCLC.

Keywords: KIAA1429; N(6)-methyladenosine (m6A); YTHDF2; YTHDF3; ZIP (ZIPK).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Adenosine / analogs & derivatives
Adenosine / genetics
Adenosine / metabolism
Animals
Carcinoma, Non-Small-Cell Lung / genetics*
Carcinoma, Non-Small-Cell Lung / pathology
Cell Proliferation / genetics
Death-Associated Protein Kinases / genetics*
Female
Gene Expression Regulation, Neoplastic / genetics
Humans
Male
Mice
Nerve Tissue Proteins / genetics*
Protein Processing, Post-Translational / genetics
RNA Splicing Factors / genetics*
RNA-Binding Proteins / genetics*
Xenograft Model Antitumor Assays

Substances

Nerve Tissue Proteins
RNA Splicing Factors
RNA-Binding Proteins
VIRMA protein, human
YTHDC1 protein, human
N-methyladenosine
DAPK3 protein, human
Death-Associated Protein Kinases
Adenosine