Anti-HIV Drug Elvitegravir Suppresses Cancer Metastasis via Increased Proteasomal Degradation of m(6)A Methyltransferase METTL3

Liao，Long1,2; He，Yan1,2; Li，Shu Jun1,2; Zhang，Guo Geng2,3; Yu，Wei3; Yang，Jing2,3; Huang，Zi Jia1; Zheng，Can Can2; He，Qing Yu1; Li，Yan4; Li，Bin2

2022-07-01

10.1158/0008-5472.CAN-21-4124

CANCER RESEARCH   Impact Factor & Quartile

0008-5472

1538-7445

N-6-methyladenosine (m(6)A) methylation is an abundant modification in eukaryotic mRNAs. Accumulating evidence suggests a role for RNA m6A methylation in various aspects of cancer biology. In this study, we aimed to explore the biological role of RNA m6A modification in tumor metastasis and to identify novel therapeutic strategies for esophageal squamous cell carcinoma (ESCC). Integration of genome-wide CRISPR/Cas9 functional screening with highly invasive and metastatic ESCC subline models led to the identification of METTL3, the catalytic subunit of the N-6-adenosine-methyltransferase complex, as a promoter of cancer metastasis. METTL3 expression was upregulated in ESCC tumors and metastatic tissues. In vitro and in vivo experiments indicated that METTL3 increased m6A in EGR1 mRNA and enhanced its stability in a YTHDF3-dependent manner, activating EGR1/Snail signaling. Investigation into the regulation of METTL3 expression found that KAT2A increased H3K27 acetylation levels in the METTL3 promoter region and activated transcription of METTL3, whereas SIRT2 exerted the opposite effects. Molecular docking and computational screening in a Food and Drug Administration- approved compound library consisting of 1,443 small molecules identified compounds targeting METTL3 to suppress cancer metastasis. Elvitegravir, originally developed to treat human immuno-deficiency virus (HIV) infection, suppressed metastasis by directly targeting METTL3 and enhancing its STUB1-mediated proteasomal degradation. Overall, RNA m(6)A modifications are important in cancer metastasis, and targeting METTL3 with elvitegravir has therapeutic potential for treating ESCC. Significance: This study finds that METTL3 promotes cancer metastasis by activating EG R1/Snail signaling in an m(6)A-dependent manner, revealing vulnerability to METTL3 blockade in esophageal squamous cell carcinoma.

SCI

English

NI Journal Papers

Others

National Key Research and Development Program of China["2021YFC2501000","2017YFA0505100"] ; National Natural Science Foundation of China["31961160727","81773085","81973339"]

Oncology

Oncology

WOS:000831504200001

AMER ASSOC CANCER RESEARCH

CLINICAL MEDICINE

2-s2.0-85133677448

Web of Science

1.MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes,Institute of Life and Health Engineering,College of Life Science and Technology,Jinan University,Guangzhou,China
2.Key Laboratory of Biological Targeting Diagnosis,Therapy and Rehabilitation of Guangdong Higher Education Institutes,Fifth Affiliated Hospital of Guangzhou Medical University,Guangzhou,China
3.MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine,National Engineering Research Center of Genetic Medicine,Institute of Biomedicine,College of Life Science and Technology,Jinan University,Guangzhou,China
4.Department of Biology,Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen Key Laboratory of Cell Microenvironment and SUSTech-HKU Joint Laboratories for Matrix Biology and Diseases,Southern University of Science and Technology,Shenzhen,China

Liao，Long,He，Yan,Li，Shu Jun,et al. Anti-HIV Drug Elvitegravir Suppresses Cancer Metastasis via Increased Proteasomal Degradation of m(6)A Methyltransferase METTL3[J]. CANCER RESEARCH,2022,82(13):2444-2457.

Liao，Long.,He，Yan.,Li，Shu Jun.,Zhang，Guo Geng.,Yu，Wei.,...&Li，Bin.(2022).Anti-HIV Drug Elvitegravir Suppresses Cancer Metastasis via Increased Proteasomal Degradation of m(6)A Methyltransferase METTL3.CANCER RESEARCH,82(13),2444-2457.

Liao，Long,et al."Anti-HIV Drug Elvitegravir Suppresses Cancer Metastasis via Increased Proteasomal Degradation of m(6)A Methyltransferase METTL3".CANCER RESEARCH 82.13(2022):2444-2457.