Lin28A and Lin28B Inhibit let-7 microRNA Biogenesis by Distinct Mechanisms

Cell. 2011 Nov 23;147(5):1066-79. doi: 10.1016/j.cell.2011.10.039.

Abstract

Lin28A and Lin28B selectively block the expression of let-7 microRNAs and function as oncogenes in a variety of human cancers. Lin28A recruits a TUTase (Zcchc11/TUT4) to let-7 precursors to block processing by Dicer in the cell cytoplasm. Here we find that unlike Lin28A, Lin28B represses let-7 processing through a Zcchc11-independent mechanism. Lin28B functions in the nucleus by sequestering primary let-7 transcripts and inhibiting their processing by the Microprocessor. The inhibitory effects of Zcchc11 depletion on the tumorigenic capacity and metastatic potential of human cancer cells and xenografts are restricted to Lin28A-expressing tumors. Furthermore, the majority of human colon and breast tumors analyzed exclusively express either Lin28A or Lin28B. Lin28A is expressed in HER2-overexpressing breast tumors, whereas Lin28B expression characterizes triple-negative breast tumors. Overall our results illuminate the distinct mechanisms by which Lin28A and Lin28B function and have implications for the development of new strategies for cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Nucleolus / metabolism
  • Cell Nucleus / metabolism
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / pathology
  • DNA-Binding Proteins / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • MicroRNAs / genetics*
  • Molecular Sequence Data
  • Neoplasm Invasiveness
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / genetics*
  • Transcription, Genetic

Substances

  • DNA-Binding Proteins
  • LIN-28 protein, human
  • LIN28B protein, human
  • MicroRNAs
  • RNA-Binding Proteins
  • TUT4 protein, human
  • mirnlet7 microRNA, human