DUSP16 promotes cancer chemoresistance through regulation of mitochondria-mediated cell death

Nat Commun. 2021 Apr 16;12(1):2284. doi: 10.1038/s41467-021-22638-7.


Drug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Fractionation
  • Cell Line, Tumor
  • Chemotherapy, Adjuvant
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use
  • Disease-Free Survival
  • Drug Resistance, Neoplasm
  • Dual-Specificity Phosphatases / analysis
  • Dual-Specificity Phosphatases / metabolism*
  • Female
  • Gene Knockdown Techniques
  • Gene Knockout Techniques
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • Middle Aged
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitogen-Activated Protein Kinase Phosphatases / analysis
  • Mitogen-Activated Protein Kinase Phosphatases / metabolism*
  • Neoplasms / mortality
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Xenograft Model Antitumor Assays
  • bcl-2-Associated X Protein / metabolism


  • Antineoplastic Agents
  • BAX protein, human
  • Biomarkers, Tumor
  • bcl-2-Associated X Protein
  • Mitogen-Activated Protein Kinase Phosphatases
  • DUSP16 protein, human
  • Dual-Specificity Phosphatases
  • Cisplatin