RHOJ controls EMT-associated resistance to chemotherapy

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Therapy resistance in cancer leads to patient mortality.
• Epithelial-to-mesenchymal transition (EMT) is linked to therapy resistance in various cancers.
• Mechanisms underlying EMT-mediated therapy resistance are not fully understood.

Purpose of the Study:

• To investigate the role of EMT in mediating resistance to anti-cancer therapies.
• To identify the molecular mechanisms driving EMT-associated therapy resistance.
• To explore RHOJ as a potential therapeutic target in resistant cancers.

Main Methods:

• Utilized a mouse model of skin squamous cell carcinoma with spontaneous EMT.
• Performed in vivo and in vitro gain and loss of function studies.
• Conducted genome-wide transcriptomic and proteomic profiling.
• Investigated RHOJ's interaction with nuclear actin regulatory proteins.

Main Results:

• EMT tumor cells exhibited high resistance to multiple anti-cancer therapies.
• RHOJ, a small GTPase highly expressed in EMT cancer cells, was identified as a key regulator of therapy resistance.
• RHOJ enhances the response to replicative stress and activates DNA damage response pathways, facilitating chemotherapy resistance.
• Inhibition of actin polymerization sensitized EMT cells to chemotherapy in a RHOJ-dependent manner.

Conclusions:

• RHOJ is a critical regulator of EMT-associated chemotherapy resistance.
• RHOJ promotes resistance by enhancing DNA repair mechanisms.
• Targeting RHOJ or actin polymerization may overcome therapy resistance in EMT-positive cancers.