A Cluster of Evolutionarily Recent KRAB Zinc Finger Proteins Protects Cancer Cells from Replicative Stress-Induced Inflammation.

Details

Serval ID
serval:BIB_26A70ECA1060
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A Cluster of Evolutionarily Recent KRAB Zinc Finger Proteins Protects Cancer Cells from Replicative Stress-Induced Inflammation.
Journal
Cancer research
Author(s)
Martins F., Rosspopoff O., Carlevaro-Fita J., Forey R., Offner S., Planet E., Pulver C., Pak H., Huber F., Michaux J., Bassani-Sternberg M., Turelli P., Trono D.
ISSN
1538-7445 (Electronic)
ISSN-L
0008-5472
Publication state
Published
Issued date
15/03/2024
Peer-reviewed
Oui
Volume
84
Number
6
Pages
808-826
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
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.
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.
Keywords
Animals, Heterochromatin/genetics, Zinc Fingers/genetics, DNA Transposable Elements, Primates/genetics, Inflammation/genetics, Neoplasms/genetics
Pubmed
Open Access
Yes
Create date
15/02/2024 17:24
Last modification date
26/03/2024 8:10
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