Micropeptide ASAP encoded by LINC00467 promotes colorectal cancer progression by directly modulating ATP synthase activity

J Clin Invest. 2021 Nov 15;131(22):e152911. doi: 10.1172/JCI152911.

Abstract

Emerging evidence has shown that open reading frames inside long noncoding RNAs (lncRNAs) could encode micropeptides. However, their roles in cellular energy metabolism and tumor progression remain largely unknown. Here, we identified a 94 amino acid-length micropeptide encoded by lncRNA LINC00467 in colorectal cancer. We also characterized its conservation across higher mammals, localization to mitochondria, and the concerted local functions. This peptide enhanced the ATP synthase construction by interacting with the subunits α and γ (ATP5A and ATP5C), increased ATP synthase activity and mitochondrial oxygen consumption rate, and thereby promoted colorectal cancer cell proliferation. Hence, this micropeptide was termed ATP synthase-associated peptide (ASAP). Furthermore, loss of ASAP suppressed patient-derived xenograft growth with attenuated ATP synthase activity and mitochondrial ATP production. Clinically, high expression of ASAP and LINC00467 predicted poor prognosis of colorectal cancer patients. Taken together, our findings revealed a colorectal cancer-associated micropeptide as a vital player in mitochondrial metabolism and provided a therapeutic target for colorectal cancer.

Keywords: Colorectal cancer; Gastroenterology; Noncoding RNAs; Oncology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis*
  • Cell Line, Tumor
  • Cell Proliferation
  • Colorectal Neoplasms / etiology*
  • Colorectal Neoplasms / pathology
  • Disease Progression
  • Humans
  • Mitochondria / metabolism
  • Mitochondrial Proteins / physiology*
  • Mitochondrial Proton-Translocating ATPases / metabolism*
  • Oxidative Phosphorylation
  • Peptides / pharmacology*
  • RNA, Long Noncoding / physiology*
  • Xenograft Model Antitumor Assays

Substances

  • Mitochondrial Proteins
  • Peptides
  • RNA, Long Noncoding
  • Adenosine Triphosphate
  • Mitochondrial Proton-Translocating ATPases