N6-methyladenosine modification in 18S rRNA promotes tumorigenesis and chemoresistance via HSF4b/HSP90B1/mutant p53 axis

Binbin Chen; Ying Huang; Shuiqing He; Peng Yu; Lirong Wu; Hao Peng

doi:10.1016/j.chembiol.2023.01.006

N⁶-methyladenosine modification in 18S rRNA promotes tumorigenesis and chemoresistance via HSF4b/HSP90B1/mutant p53 axis

Cell Chem Biol. 2023 Feb 16;30(2):144-158.e10. doi: 10.1016/j.chembiol.2023.01.006.

Authors

Binbin Chen¹, Ying Huang², Shuiqing He², Peng Yu³, Lirong Wu⁴, Hao Peng⁵

Affiliations

¹ Department of Breast Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 106 Zhongshan Er Road, Yuexiu District, Guangzhou 510080, P.R. China; State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China; Department of Clinical Nutrition, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
² State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
³ Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou 510095, P.R. China.
⁴ Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, P.R. China. Electronic address: wulirong126@126.com.
⁵ Department of Breast Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 106 Zhongshan Er Road, Yuexiu District, Guangzhou 510080, P.R. China. Electronic address: pengh67@mail.sysu.edu.cn.

PMID: 36800991
DOI: 10.1016/j.chembiol.2023.01.006

Abstract

Aberrant N⁶-methyladenosine (m⁶A) modification on mRNA is correlated with cancer progression. However, the role of m⁶A on ribosomal RNA (rRNA) in cancer remains poorly understood. Our current study reveals that METTL5/TRMT112 and their mediated m⁶A modification at the 18S rRNA 1832 site (m⁶A₁₈₃₂) are elevated in nasopharyngeal carcinoma (NPC) and promote oncogenic transformation in vitro and in vivo. Moreover, loss of catalytic activity of METTL5 abolishes its oncogenic functions. Mechanistically, m⁶A₁₈₃₂ 18S rRNA modification facilitates the assembly of 80S ribosome via bridging the RPL24-18S rRNA interaction, therefore promoting the translation of mRNAs with 5' terminal oligopyrimidine (5' TOP) motifs. Further mechanistic analysis reveals that METTL5 enhances HSF4b translation to activate the transcription of HSP90B1, which binds with oncogenic mutant p53 (mutp53) protein and prevents it from undergoing ubiquitination-dependent degradation, therefore facilitating NPC tumorigenesis and chemoresistance. Overall, our findings uncover an innovative mechanism underlying rRNA epigenetic modification in regulating mRNA translation and the mutp53 pathway in cancer.

Keywords: 18S rRNA; METTL5; m(6)A modification; mutant p53; nasopharyngeal carcinoma.

Publication types

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

MeSH terms

Carcinogenesis / genetics
Drug Resistance, Neoplasm* / genetics
Humans
Methyltransferases / genetics
Methyltransferases / metabolism
RNA, Ribosomal, 18S / genetics
RNA, Ribosomal, 18S / metabolism
Tumor Suppressor Protein p53* / genetics
Tumor Suppressor Protein p53* / metabolism

Substances

RNA, Ribosomal, 18S
Tumor Suppressor Protein p53
N-methyladenosine
TRMT112 protein, human
Methyltransferases