2. Academic Validation
  3. Targeting KDM4A epigenetically activates tumor-cell-intrinsic immunity by inducing DNA replication stress

Targeting KDM4A epigenetically activates tumor-cell-intrinsic immunity by inducing DNA replication stress

  • Mol Cell. 2021 May 20;81(10):2148-2165.e9. doi: 10.1016/j.molcel.2021.02.038.
Wuchang Zhang 1,  Wei Liu 1,  Lingfei Jia 1,  Demeng Chen 1,  Insoon Chang 1,  Michael Lake 2,  Laurent A Bentolila 2,  Cun-Yu Wang 3
Affiliations

Affiliations

  • 1 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 2 Advanced Light Microscopy and Spectroscopy Laboratory, California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 3 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: cwang@dentistry.ucla.edu.
PMID: 33743195 DOI: 10.1016/j.molcel.2021.02.038
Abstract

Developing strategies to activate tumor-cell-intrinsic immune response is critical for improving tumor immunotherapy by exploiting tumor vulnerability. KDM4A, as a histone H3 lysine 9 trimethylation (H3K9me3) demethylase, has been found to play a critical role in squamous cell carcinoma (SCC) growth and metastasis. Here we report that KDM4A inhibition promoted heterochromatin compaction and induced DNA replication stress, which elicited antitumor immunity in SCC. Mechanistically, KDM4A inhibition promoted the formation of liquid-like HP1γ puncta on heterochromatin and stall DNA replication, which activated tumor-cell-intrinsic cGAS-STING signaling through replication-stress-induced cytosolic DNA accumulation. Moreover, KDM4A inhibition collaborated with PD1 blockade to inhibit SCC growth and metastasis by recruiting and activating CD8+ T cells. In vivo lineage tracing demonstrated that KDM4A inhibition plus PD1 blockade efficiently eliminated Cancer Stem Cells. Altogether, our results demonstrate that targeting KDM4A can activate anti-tumor immunity and enable PD1 blockade immunotherapy by aggravating replication stress in SCC cells.

Keywords

DNA replication stress; H3K9me3; KDM4A; PD-1 blockade; Phase separation; cancer stem cells; head and neck squamous cell carcinoma; heterochromatin condensates; immune surveillance; metastasis.

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