MIR34A regulates autophagy and apoptosis by targeting HMGB1 in the retinoblastoma cell

Ke Liu, Jun Huang, Min Xie, Yan Yu, Shan Zhu, Rui Kang, Lizhi Cao, Daolin Tang, Xuanchu Duan

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

MIR34A (microRNA 34a) is a tumor suppressor gene, but how it regulates chemotherapy response and resistance is not completely understood. Here, we show that the microRNA MIR34A-dependent high mobility group box 1 (HMGB1) downregulation inhibits autophagy and enhances chemotherapy-induced apoptosis in the retinoblastoma cell. HMGB1 is a multifaceted protein with a key role in autophagy, a self-degradative, homeostatic process with a context-specific role in cancer. MIR34A inhibits HMGB1 expression through a direct MIR34A-binding site within the HMGB1 3′ untranslated region. MIR34A inhibition of HMGB1 leads to a decrease in autophagy under starvation conditions or chemotherapy treatment. Inhibition of autophagy promotes oxidative injury and DNA damage and increases subsequent CASP3 activity, CASP3 cleavage, and PARP1 [poly (ADP-ribose) polymerase 1] cleavage, which are important to the apoptotic process. Finally, upregulation of MIR34A, knockdown of HMGB1, or inhibition of autophagy (e.g., knockdown of ATG5 and BECN1) restores chemosensitivity and enhances tumor cell death in the retinoblastoma cell. These data provide new insights into the mechanisms governing the regulation of HMGB1 expression by microRNA and their possible contribution to autophagy and drug resistance.

Original languageEnglish (US)
Pages (from-to)442-452
Number of pages11
JournalAutophagy
Volume10
Issue number3
DOIs
StatePublished - Mar 2014
Externally publishedYes

Keywords

  • Apoptosis
  • Autophagy
  • Chemotherapy
  • Hmbg1
  • MicroRNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'MIR34A regulates autophagy and apoptosis by targeting HMGB1 in the retinoblastoma cell'. Together they form a unique fingerprint.

Cite this