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Updated: Jan 28, 2026

Analyzing Starvation-Induced Autophagy in the Drosophila melanogaster Larval Fat Body
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Nrf2-miR-129-3p-mTOR Axis Controls an miRNA Regulatory Network Involved in HDACi-Induced Autophagy

Weijian Sun1, Yongdong Yi1, Guojun Xia1

  • 1Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejian 325027, China.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|March 11, 2019
PubMed

Insights

Histone deacetylase inhibitors (HDACis) can cause chemoresistance via the Nrf2 pathway. This study shows inhibiting Nrf2 or miR-129-3p enhances HDACi cancer treatment by blocking autophagy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Histone deacetylase inhibitors (HDACis) are used for solid tumors but face clinical resistance.
  • Nuclear factor erythroid 2 like-2 (Nrf2) is implicated in chemoresistance, potentially through autophagy regulation.

Purpose of the Study:

  • To elucidate the molecular mechanisms of Nrf2-mediated chemoresistance to HDACis.
  • To identify novel therapeutic targets for overcoming HDACi resistance.

Main Methods:

  • Investigated Nrf2 and autophagy in cancer cells treated with HDACis.
  • Utilized Nrf2 knockdown/inhibition and microRNA (miRNA) array analysis.
  • Confirmed miR-129-3p as an Nrf2 target and mammalian target of rapamycin (mTOR) as a miR-129-3p target.

Main Results:

  • HDACi treatment increased Nrf2 levels and activity, inducing autophagy.
  • Nrf2 controlled autophagy via upregulation of miR-129-3p, which targets mTOR.
  • Inhibiting Nrf2 or miR-129-3p enhanced HDACi-induced cancer cell death in vitro and in vivo.

Conclusions:

  • Nrf2 regulates mTOR-mediated autophagy through miR-129-3p in response to HDACis.
  • Targeting the Nrf2/miR-129-3p/mTOR pathway may overcome HDACi resistance.
  • This pathway inhibition offers a strategy to improve HDACi-based cancer therapy.
Keywords:
HDACiNrf2autophagymiR-129-3p

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