let-7 Modulates Chromatin Configuration and Target Gene Repression through Regulation of the ARID3B Complex

Cell Rep. 2016 Jan 26;14(3):520-533. doi: 10.1016/j.celrep.2015.12.064. Epub 2016 Jan 14.

Abstract

Let-7 is crucial for both stem cell differentiation and tumor suppression. Here, we demonstrate a chromatin-dependent mechanism of let-7 in regulating target gene expression in cancer cells. Let-7 directly represses the expression of AT-rich interacting domain 3B (ARID3B), ARID3A, and importin-9. In the absence of let-7, importin-9 facilitates the nuclear import of ARID3A, which then forms a complex with ARID3B. The nuclear ARID3B complex recruits histone demethylase 4C to reduce histone 3 lysine 9 trimethylation and promotes the transcription of stemness factors. Functionally, expression of ARID3B is critical for the tumor initiation in let-7-depleted cancer cells. An inverse association between let-7 and ARID3A/ARID3B and prognostic significance is demonstrated in head and neck cancer patients. These results highlight a chromatin-dependent mechanism where let-7 regulates cancer stemness through ARID3B.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line
  • Chromatin / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Female
  • Histones / metabolism
  • Humans
  • Karyopherins / chemistry
  • Karyopherins / genetics
  • Karyopherins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasms / metabolism
  • Neoplasms / mortality
  • Neoplasms / pathology
  • Octamer Transcription Factor-3 / genetics
  • Oligonucleotides, Antisense / metabolism
  • RNA Interference
  • Sequence Alignment
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptome
  • Transplantation, Heterologous

Substances

  • ARID3A protein, human
  • ARID3B protein, human
  • Chromatin
  • DNA-Binding Proteins
  • Histones
  • Karyopherins
  • MicroRNAs
  • Octamer Transcription Factor-3
  • Oligonucleotides, Antisense
  • POU5F1 protein, human
  • Transcription Factors
  • importin 9, human
  • mirnlet7 microRNA, human