Journal article
Oncogene SETDB1's dual role: driving tumor progression and immune escape
Oncogene, 42542437
08/01/2026
DOI: 10.1038/s41388-026-03911-9
PMID: 42542437
Appears in UI Libraries Support Open Access
Abstract
Oncogene SETDB1, an H3K9 methyltransferase, drives tumorigenesis in various cancers. Using endometrial cancer (EC) as a model, we discovered SETDB1's dual mechanisms in driving EC tumorigenesis and mediating immune evasion. SETDB1 knockout (SETDB1-/-) tumor-bearing mice exhibited prolonged survival up to 100 days. Transcriptomic profiling of SETDB1-/- EC cells revealed decreased oncogene expression and increased tumor suppressor gene expression, which indicates that SETDB1 intrinsically promotes EC proliferation by regulating these downstream genes. SETDB1 repressed repeat elements and the interferon pathway, mediating immune evasion extrinsically by inhibiting anti-tumor macrophage infiltration. ChIP-seq analysis showed SETDB1 binding at pericentromeric regions on many chromosomes and numerous ZNFs. Loss of SETDB1 resulted in abnormal cell division. SETDB1-/- tumors displayed reduced proliferation markers (Ki67, pHH3) and increased macrophage infiltration. Mechanistically, SETDB1 promotes CD47 (a don't-eat-me signal) and represses CCL5 and CXCL9 (macrophage and T-cell recruiting chemokines), contributing to immune evasion. M1-like macrophages killed more SETDB1-/- cells in co-culture. Additionally, SETDB1 knockout in mouse EC cells reduced tumor growth in C57BL/6 mice, with increased macrophage and CD4 + T-cell infiltration. Our results indicate that elevated SETDB1 and its targets can predict higher tumor grade and worse survival, suggesting that targeting SETDB1 could be a promising therapeutic strategy for EC.
Details
- Title: Subtitle
- Oncogene SETDB1's dual role: driving tumor progression and immune escape
- Creators
- Kiarash Salari - University of Iowa, PathologyJiaqing Hao - University of Iowa, PathologyRyan Jilek - University of Iowa, PathologyMatthew Wells - University of IowaTianyue Li - Univ Iowa, Carver Coll Med, Dept Pathol, Iowa, IA 52242 USAEleanor Johnson - University of IowaWendy Meng - University of IowaHuiyaxin Wang - University of IowaEthan Zibble - University of IowaAdam Allen - University of IowaJack Gilbert - University of IowaRyan McLerran - University of IowaEmma Schuett - University of IowaClaudia Oliva - University of Iowa, Radiation OncologyCorinne E. Griguer - University of Iowa, Radiation OncologyDavid K. Meyerholz - University of Iowa, PathologyMelinda S. Yates - University of North Carolina at Chapel HillHenry L. Keen - University of Iowa, Iowa Institute of Human GeneticsXiangbing Meng - University of Iowa, PathologyYiqin Xiong - Boston UniversityBing Li - University of Iowa, PathologyShujie Yang - University of Iowa, Pathology
- Resource Type
- Journal article
- Publication Details
- Oncogene, 42542437
- DOI
- 10.1038/s41388-026-03911-9
- PMID
- 42542437
- NLM abbreviation
- Oncogene
- ISSN
- 0950-9232
- eISSN
- 1476-5594
- Publisher
- Springer Nature
- Number of pages
- 23
- Grant note
- U01CA272424 / U.S. Department of Health & Human Services | National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; Office of the Administrator (NIH) R37CA238274; P30CA086862; U01CA272424 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
- Language
- English
- Electronic publication date
- 08/01/2026
- Academic Unit
- Pathology; Surgery; Radiation Oncology; Iowa Institute of Human Genetics
- Record Identifier
- 9985217633302771
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