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EZH2 regulates tumor-associated macrophages by the KDM6A-mediated inflammatory response in HPV16-positive cervical

Qing Tang1, Ying Yang2, Jia'nan Sun3

  • 1Department of Gynecology, Yantai Yuhuangding Hospital, No.20, Yuhuangding East Road, Yantai, 264000, China.

Human Cell
|June 19, 2025
PubMed

Insights

Enhancer of zeste homolog 2 (EZH2) inhibition suppresses tumor growth in HPV16-positive cervical cancer by regulating KDM6A and M2 macrophage polarization. This finding offers insights into immune modulation strategies for cervical cancer treatment.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • High-risk human papillomavirus (HPV) subtypes influence the immune response in cervical cancer.
  • Tumor-associated macrophages (TAMs) play a crucial role in tumor development by modulating the immune response.
  • The role of enhancer of zeste homolog 2 (EZH2) in TAM-mediated immune regulation within HPV16-positive cervical cancer requires elucidation.

Purpose of the Study:

  • To investigate the mechanism by which EZH2 influences TAMs in HPV16-positive cervical cancer.
  • To analyze the impact of EZH2 inhibition on KDM6A expression, inflammatory responses, and M2 macrophage polarization in HPV16-positive cervical cancer cells.
  • To evaluate the therapeutic potential of EZH2 inhibition in reducing tumor growth in vivo.

Main Methods:

  • HPV16-positive cervical cancer cell lines (SiHa, CaSki) were treated with an EZH2 inhibitor (EPZ6438).
  • KDM6A expression, cell viability, inflammatory cytokine levels (IL-6, CXCL1), and Akt signaling were assessed.
  • M2 macrophage polarization was studied via co-culture experiments, and tumor growth was evaluated in a nude mouse model.

Main Results:

  • EZH2 inhibition suppressed cell viability and inflammatory responses by downregulating KDM6A in HPV16-positive cervical cancer cells.
  • Overexpression of KDM6A counteracted the effects of EZH2 inhibition on cell viability and inflammation.
  • EZH2 inhibition reduced M2 macrophage polarization, linked to KDM6A-mediated inflammatory responses, and decreased tumor growth in vivo.

Conclusions:

  • EZH2 inhibition exerts anti-tumor effects in HPV16-positive cervical cancer by suppressing KDM6A and modulating the inflammatory response.
  • The mechanism involves KDM6A-mediated regulation of inflammatory pathways, impacting M2 macrophage polarization and subsequent tumor growth.
  • EZH2 inhibition represents a potential therapeutic strategy for HPV16-positive cervical cancer through immune modulation.
Keywords:
Cervical cancerKDM6ATumor-associated macrophages

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