2. Academic Validation
  3. YAP 5-methylcytosine modification increases its mRNA stability and promotes the transcription of exosome secretion-related genes in lung adenocarcinoma

YAP 5-methylcytosine modification increases its mRNA stability and promotes the transcription of exosome secretion-related genes in lung adenocarcinoma

  • Cancer Gene Ther. 2022 Sep 19. doi: 10.1038/s41417-022-00533-7.
Wenjun Yu  # 1,  Congcong Zhang  # 2,  Yikun Wang 1,  Xiaoting Tian 3,  Yayou Miao 3,  Fanyu Meng 3,  Lifang Ma 4,  Xiao Zhang 5,  Jinjing Xia 6
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 200030, Shanghai, China.
  • 2 Anhui University of Science and Technology School of Medicine, Huainan, 232001, Anhui, China.
  • 3 Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 200030, Shanghai, China.
  • 4 Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 200030, Shanghai, China. [email protected].
  • 5 Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 200030, Shanghai, China. [email protected].
  • 6 Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 200030, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 36123390 DOI: 10.1038/s41417-022-00533-7
Abstract

YAP is a transcriptional co-activator with critical roles in tumorigenesis. However, its upstream regulatory mechanism, especially how its mRNA stability is regulated, remains to be further studied. Here, we validated that YAP expression was higher in lung adenocarcinoma (LUAD) tissues compared to adjacent normal tissues, and found that YAP m5C modification occurred in its 328-331 3' UTR region under the promotion NSUN2 and ALYREF, and increased the stability of YAP mRNA. This m5C modification also inhibited miR-582-3p binding and m6A modification in the nearby region. In addition, YAP m5C modification enhanced the exosome secretion effect, which was caused by two YAP-dependent transcription factors, Mycn and SOX10, and then stimulating the transcription of seven downstream exosome-promoting genes. Furthermore, we found that YAP m5C modification and its exosome-secretion-promoting function contributed to the malignant phenotype and AZD9291 (a third-generation EGFR-TKI) resistance of LUAD cells. Collectively, YAP is promoted by its m5C modification, and blocking YAP m5C modification will be helpful for future LUAD treatment.

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