Long noncoding RNA LINC02582 acts downstream of miR-200c to promote radioresistance through CHK1 in breast cancer cells

Cell Death Dis. 2019 Oct 10;10(10):764. doi: 10.1038/s41419-019-1996-0.

Abstract

Radiotherapy is essential to treat breast cancer and microRNA (miRNA) miR-200c is considered as a radiosensitizer of breast cancer. However, the molecular mechanisms by which miR-200c regulates radiosensitivity remain largely unknown. In the present study, we showed that induction of miR-200c led to widespread alteration in long noncoding RNA (lncRNA) expression in breast cancer cells. We identified lncRNA LINC02582 as a target of miR-200c. Inhibition of LINC02582 expression increased radiosensitvity, while overexpression of LINC02582 promoted radioresistance. Mechanistically, LINC02582 interacts with deubiquitinating enzyme ubiquitin specific peptidase 7 (USP7) to deubiquitinate and stabilize checkpoint kinase 1 (CHK1), a critical effector kinase in DNA damage response, thus promoting radioresistance. Furthermore, we detected an inverse correlation between the expression of miR-200c vs. LINC02582 and CHK1 in breast cancer samples. These findings identified LINC02582 as a downstream target of miR-200c linking miR-200c to CHK1, in which miR-200c increases radiosensitivity by downregulation of CHK1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / radiotherapy
  • Cell Line, Tumor
  • Checkpoint Kinase 1 / genetics
  • Checkpoint Kinase 1 / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Humans
  • Mass Spectrometry
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Small Interfering
  • Radiation Tolerance / genetics*
  • Radiation Tolerance / radiation effects
  • Radiation-Sensitizing Agents / therapeutic use
  • Transplantation, Heterologous
  • Ubiquitin / metabolism
  • Ubiquitin-Specific Peptidase 7 / genetics
  • Ubiquitin-Specific Peptidase 7 / metabolism

Substances

  • MIRN200 microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • RNA, Small Interfering
  • Radiation-Sensitizing Agents
  • Ubiquitin
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • USP7 protein, human
  • Ubiquitin-Specific Peptidase 7