Downregulated METTL14 accumulates BPTF that reinforces super-enhancers and distal lung metastasis via glycolytic reprogramming in renal cell carcinoma

Theranostics. 2021 Jan 26;11(8):3676-3693. doi: 10.7150/thno.55424. eCollection 2021.

Abstract

Background: Methyltransferase-like 14 (METTL14) participates in tumorigenesis in several malignancies, but how METTL14 mediates the metastasis of renal cell carcinoma (RCC) has never been reported. Methods: Western blotting, quantitative real-time PCR, and immunohistochemistry were used to determine the mRNA and protein levels of relevant genes. Methylated RNA immunoprecipitation sequencing and RNA sequencing were utilized to screen potential targets of METTL14. Chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin sequencing were performed to investigate epigenetic alterations. The biological roles and mechanisms of METTL14/BPTF in promoting lung metastasis were confirmed in vitro and in vivo using cell lines, patient samples, xenograft models, and organoids. Results: Utilizing the TCGA-KIRC and Ruijin-RCC datasets, we found low expression of METTL14 in mRCC samples, which predicted poor prognosis. METTL14 deficiency promoted RCC metastasis in vitro and in vivo. Mechanistically, METTL14-mediated m6A modification negatively regulated the mRNA stability of bromodomain PHD finger transcription factor (BPTF) and depended on BPTF to drive lung metastasis. Accumulated BPTF in METTL14-deficient cells remodeled the enhancer landscape to reinforce several oncogenic crosstalk. Particularly, BPTF constituted super-enhancers that activate downstream targets like enolase 2 and SRC proto-oncogene nonreceptor tyrosine kinase, leading to glycolytic reprogramming of METTL14-/- cells. Finally, we determined the efficacy of the BPTF inhibitor AU1 in suppressing mRCC of patient-derived cells, mRCC-derived organoids (MDOs), and orthotopic xenograft models. Conclusions: Our study is the first to investigate the essential role of m6A modification and the METTL14/BPTF axis in the epigenetic and metabolic remodeling of mRCC, highlighting AU1 as a vital therapeutic candidate.

Keywords: BPTF; METTL14; glycolysis; metastatic RCC; super-enhancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / analogs & derivatives
  • Animals
  • Antigens, Nuclear / genetics*
  • Antigens, Nuclear / metabolism*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / secondary
  • Cell Line, Tumor
  • Down-Regulation
  • Enhancer Elements, Genetic
  • Gene Knockout Techniques
  • Glycolysis
  • Humans
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Male
  • Methyltransferases / antagonists & inhibitors
  • Methyltransferases / genetics*
  • Methyltransferases / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Phenylurea Compounds
  • Precision Medicine
  • Prognosis
  • Proto-Oncogene Mas
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • 1-(2-adamantyl)-3-(2,3,4-trifluorophenyl)urea
  • Antigens, Nuclear
  • Biomarkers, Tumor
  • MAS1 protein, human
  • Nerve Tissue Proteins
  • Phenylurea Compounds
  • Proto-Oncogene Mas
  • RNA, Messenger
  • Transcription Factors
  • fetal Alzheimer antigen
  • METTL14 protein, human
  • Methyltransferases
  • Adamantane