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Targeting KDM4A epigenetically activates tumor-cell-intrinsic immunity by inducing DNA replication stress.
Zhang, Wuchang; Liu, Wei; Jia, Lingfei; Chen, Demeng; Chang, Insoon; Lake, Michael; Bentolila, Laurent A; Wang, Cun-Yu.
Afiliação
  • Zhang W; 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.
  • Liu W; 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.
  • Jia L; 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.
  • Chen D; 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.
  • Chang I; 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.
  • Lake M; Advanced Light Microscopy and Spectroscopy Laboratory, California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Bentolila LA; Advanced Light Microscopy and Spectroscopy Laboratory, California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Wang CY; 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, Henr
Mol Cell ; 81(10): 2148-2165.e9, 2021 05 20.
Article em En | MEDLINE | ID: mdl-33743195
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Estresse Fisiológico / Carcinoma de Células Escamosas / Epigênese Genética / Replicação do DNA / Histona Desmetilases / Histona Desmetilases com o Domínio Jumonji / Imunidade Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Estresse Fisiológico / Carcinoma de Células Escamosas / Epigênese Genética / Replicação do DNA / Histona Desmetilases / Histona Desmetilases com o Domínio Jumonji / Imunidade Idioma: En Ano de publicação: 2021 Tipo de documento: Article