RHOJ controls EMT-associated resistance to chemotherapy

Nature. 2023 Apr;616(7955):168-175. doi: 10.1038/s41586-023-05838-7. Epub 2023 Mar 22.


The resistance of cancer cells to therapy is responsible for the death of most patients with cancer1. Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in different cancer cells2,3. However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma undergoing spontaneous EMT during tumorigenesis, we found that EMT tumour cells are highly resistant to a wide range of anti-cancer therapies both in vivo and in vitro. Using gain and loss of function studies in vitro and in vivo, we found that RHOJ-a small GTPase that is preferentially expressed in EMT cancer cells-controls resistance to therapy. Using genome-wide transcriptomic and proteomic profiling, we found that RHOJ regulates EMT-associated resistance to chemotherapy by enhancing the response to replicative stress and activating the DNA-damage response, enabling tumour cells to rapidly repair DNA lesions induced by chemotherapy. RHOJ interacts with proteins that regulate nuclear actin, and inhibition of actin polymerization sensitizes EMT tumour cells to chemotherapy-induced cell death in a RHOJ-dependent manner. Together, our study uncovers the role and the mechanisms through which RHOJ acts as a key regulator of EMT-associated resistance to chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / drug effects
  • Actins / metabolism
  • Animals
  • Carcinoma, Squamous Cell* / drug therapy
  • Carcinoma, Squamous Cell* / metabolism
  • Carcinoma, Squamous Cell* / pathology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • Epithelial-Mesenchymal Transition* / drug effects
  • Gene Expression Profiling
  • Genome
  • Mice
  • Proteomics
  • Skin Neoplasms* / drug therapy
  • Skin Neoplasms* / metabolism
  • Skin Neoplasms* / pathology
  • rho GTP-Binding Proteins* / genetics
  • rho GTP-Binding Proteins* / metabolism


  • Actins
  • rho GTP-Binding Proteins
  • Rhoj protein, mouse