WTAP-mediated m6A modification of lncRNA DIAPH1-AS1 enhances its stability to facilitate nasopharyngeal carcinoma growth and metastasis

Zhi-Xuan Li; Zi-Qi Zheng; Pan-Yang Yang; Li Lin; Guan-Qun Zhou; Jia-Wei Lv; Lu-Lu Zhang; FoPing Chen; Ying-Qin Li; Chen-Fei Wu; Feng Li; Jun Ma; Na Liu; Ying Sun

doi:10.1038/s41418-021-00905-w

WTAP-mediated m⁶A modification of lncRNA DIAPH1-AS1 enhances its stability to facilitate nasopharyngeal carcinoma growth and metastasis

Cell Death Differ. 2022 Jun;29(6):1137-1151. doi: 10.1038/s41418-021-00905-w. Epub 2022 Jan 8.

Authors

Zhi-Xuan Li^#¹, Zi-Qi Zheng^#¹, Pan-Yang Yang^#¹, Li Lin^#¹, Guan-Qun Zhou^#¹, Jia-Wei Lv¹, Lu-Lu Zhang², FoPing Chen¹, Ying-Qin Li¹, Chen-Fei Wu¹, Feng Li¹, Jun Ma¹, Na Liu³, Ying Sun⁴

Affiliations

¹ State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P.R. China.
² State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P.R. China.
³ State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P.R. China. liun1@sysucc.org.cn.
⁴ State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P.R. China. sunying@sysucc.org.cn.

^# Contributed equally.

Abstract

As the most predominant RNA epigenetic regulation in eukaryotic cells, N⁶-methyladenosine (m⁶A) plays a critical role in human tumorigenesis and cancer progression. However, the biological function and molecular mechanism of m⁶A regulation in naso-pharyngeal carcinoma (NPC) remain elusive. Here, we showed that Wilms' tumor 1-associating protein (WTAP) expression was apparently upregulated in NPC, and increased WTAP was associated with poor prognosis. WTAP upregulated in NPC was fine-tuned by KAT3A-mediated H3K27 acetylation. Functionally, WTAP was required for the growth and metastasis of NPC. Mechanistically, lncRNA DIAPH1-AS1 was identified as a bona fide m⁶A target of WTAP. WTAP-mediated m⁶A modification of DIAPH1-AS1 enhanced its stability relying on the m⁶A reader IGF2BP2-dependent pathway. Furthermore, DIAPH1-AS1 acted as a molecular adaptor that promoted MTDH-LASP1 complex formation and upregulated LASP1 expression, ultimately facilitating NPC growth and metastasis. Thus, WTAP-mediated DIAPH1-AS1 m⁶A methylation is required for NPC tumorigenesis and metastasis.

Publication types

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

MeSH terms

Adaptor Proteins, Signal Transducing
Adenosine / analogs & derivatives*
Adenosine / genetics
Adenosine / metabolism
Carcinogenesis
Cell Cycle Proteins* / genetics
Cell Cycle Proteins* / metabolism
Cell Line, Tumor
Cell Proliferation / physiology
Cytoskeletal Proteins / genetics
Cytoskeletal Proteins / metabolism
Epigenesis, Genetic
Formins* / genetics
Formins* / metabolism
Humans
LIM Domain Proteins / genetics
LIM Domain Proteins / metabolism
Membrane Proteins / genetics
Membrane Proteins / metabolism
Nasopharyngeal Carcinoma* / genetics
Nasopharyngeal Carcinoma* / metabolism
Nasopharyngeal Carcinoma* / pathology
Nasopharyngeal Neoplasms* / genetics
Nasopharyngeal Neoplasms* / metabolism
Nasopharyngeal Neoplasms* / pathology
Neoplasm Metastasis
RNA Splicing Factors* / genetics
RNA Splicing Factors* / metabolism
RNA, Long Noncoding* / genetics
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Cytoskeletal Proteins
Formins
IGF2BP2 protein, human
LASP1 protein, human
LIM Domain Proteins
MTDH protein, human
Membrane Proteins
RNA Splicing Factors
RNA, Long Noncoding
RNA-Binding Proteins
WTAP protein, human
N-methyladenosine
Adenosine