2024-02-13 スイス連邦工科大学ローザンヌ校(EPFL)
<関連情報>
- https://actu.epfl.ch/news/exposing-hiding-lymphoma-cells-to-the-immune-syste/
- https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-23-1237/734231/A-Cluster-of-Evolutionarily-Recent-KRAB-Zinc
進化的に新しいKRABジンクフィンガータンパク質のクラスターが、複製ストレスによる炎症からがん細胞を守る A Cluster of Evolutionarily Recent KRAB Zinc Finger Proteins Protects Cancer Cells from Replicative Stress–Induced Inflammation
Filipe Martins;Olga Rosspopoff;Joana Carlevaro-Fita;Romain Forey;Sandra Offner;Evarist Planet;Cyril Pulver;HuiSong Pak;Florian Huber;Justine Michaux;Michal Bassani-Sternberg;Priscilla Turelli;Didier Trono
Cancer Research Published:February 12 2024
DOI:https://doi.org/10.1158/0008-5472.CAN-23-1237
Abstract
Heterochromatin loss and genetic instability enhance cancer progression by favoring clonal diversity, yet uncontrolled replicative stress leads to mitotic catastrophe and inflammatory responses that promote immune rejection. KRAB domain-containing zinc finger proteins (KZFP) contribute to heterochromatin maintenance at transposable elements (TE). Here, we identified an association of upregulation of a cluster of primate-specific KZFPs with poor prognosis, increased copy-number alterations, and changes in the tumor microenvironment in diffuse large B-cell lymphoma (DLBCL). Depleting two of these KZFPs targeting evolutionarily recent TEs, ZNF587 and ZNF417, impaired the proliferation of cells derived from DLBCL and several other tumor types. ZNF587 and ZNF417 depletion led to heterochromatin redistribution, replicative stress, and cGAS–STING-mediated induction of an interferon/inflammatory response, which enhanced susceptibility to macrophage-mediated phagocytosis and increased surface expression of HLA-I, together with presentation of a neoimmunopeptidome. Thus, cancer cells can exploit KZFPs to dampen TE-originating surveillance mechanisms, which likely facilitates clonal expansion, diversification, and immune evasion.
Significance:
Upregulation of a cluster of primate-specific KRAB zinc finger proteins in cancer cells prevents replicative stress and inflammation by regulating heterochromatin maintenance, which could facilitate the development of improved biomarkers and treatments.
