Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development

Area of Science:

• Molecular Biology
• Cellular Signaling
• Cancer Research

Background:

• Epidermal growth factor receptor (EGFR) signaling drives cell proliferation and differentiation.
• EGFR overexpression/mutations are common in solid tumors, correlating with poor prognosis.
• The precise signaling axis for EGFR-mediated NF-κB activation in tumors remains unclear.

Purpose of the Study:

• To elucidate the signaling axis responsible for EGFR-mediated NF-κB activation.
• To investigate the role of plakophilin 2 (PKP2) and the linear ubiquitin chain assembly complex (LUBAC) in this pathway.
• To evaluate the therapeutic potential of targeting this axis in cancer.

Main Methods:

• Investigated EGFR-mediated NF-κB activation using EGF stimulation.
• Utilized plakophilin 2 (PKP2) and LUBAC components, including HOIP.
• Employed gene knockout (HOIP) and pharmacological inhibition (HOIPIN-8) in cancer cell lines and xenograft models.

Main Results:

• PKP2 and LUBAC are essential for EGFR-mediated NF-κB activation.
• EGFR recruits PKP2, which activates LUBAC, leading to NEMO linear ubiquitination and NF-κB activation.
• HOIP knockout significantly reduced tumor cell proliferation and xenograft tumor growth (>70%).
• HOIPIN-8 inhibited NF-κB activation and proliferation in multiple cancer cell lines.

Conclusions:

• A novel linear ubiquitination signaling axis involving EGFR, PKP2, and LUBAC has been identified.
• This pathway is critical for EGF-induced NF-κB activation, cell proliferation, and tumor development.
• Targeting HOIP E3 ubiquitin ligase activity presents a potential therapeutic strategy for cancer treatment.