SETDB1 cooperates with the CRL4B complex to promote colorectal cancer tumorigenesis by disrupting circadian rhythm
- 1State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- 2Institute of Cancer Research, Henan Academy of Innovations in Medical Sciences, Zhengzhou, China
Abstract
The circadian rhythm is an intrinsic, self-regulatory physiological system in organisms that is hierarchically governed by core clock genes. Dysregulation of this rhythm is closely associated with tumor progression. However, the specific molecular mechanisms underlying circadian rhythm disruption–mediated colorectal cancer (CRC) remain largely elusive. The histone methyltransferase SET domain bifurcated 1 (SETDB1) exerts oncogenic functions in multiple solid tumors, prompting this study to investigate the molecular mechanisms through which SETDB1 regulates CRC progression. Our results demonstrate that SETDB1 acts as an oncogene in CRC by interacting with the Cullin 4B-RING E3 ligase (CRL4B) complex to enhance cancer cell proliferation, invasion, and stemness maintenance. Specifically, SETDB1 and the CRL4B complex assemble into a transcriptional repressor complex that binds to the promoters of core clock genes, such as PER3 and CRY1, to repress their transcription, thereby disrupting cellular circadian rhythms and ultimately accelerating CRC cell proliferation and metastasis. Collectively, our findings elucidate the pivotal role of the SETDB1/CRL4B complex in CRC pathogenesis and provide a potential therapeutic strategy targeting SETDB1 for patients with CRC with high CUL4B expression.
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BibTeX
@article{zhang2026setdb1,
title = {{SETDB1 cooperates with the CRL4B complex to promote colorectal cancer tumorigenesis by disrupting circadian rhythm}},
author = {Min Zhang and Dong Yan and Jingyao Zhang and Tianyang Gao and Jingwen Cai and Ting Hu and Tianyu Ma and Yinuo Wang and Miaomiao Huo and Die Zhang and Yu Li and Jingjing Zhang and Chang Guo and Xinhui Hao and Tian Zhu and Jiayi Gao and Zengwei Tang and Baowen Yuan and Yan Wang},
journal = {Oncogene},
year = {2026},
month = sep,
doi = {10.1038/s41388-026-03972-w},
url = {https://doi.org/10.1038/s41388-026-03972-w},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - SETDB1 cooperates with the CRL4B complex to promote colorectal cancer tumorigenesis by disrupting circadian rhythm
AU - Min Zhang
AU - Dong Yan
AU - Jingyao Zhang
AU - Tianyang Gao
AU - Jingwen Cai
AU - Ting Hu
AU - Tianyu Ma
AU - Yinuo Wang
AU - Miaomiao Huo
AU - Die Zhang
AU - Yu Li
AU - Jingjing Zhang
AU - Chang Guo
AU - Xinhui Hao
AU - Tian Zhu
AU - Jiayi Gao
AU - Zengwei Tang
AU - Baowen Yuan
AU - Yan Wang
PY - 2026
DA - 2026/09/23
JO - Oncogene
DO - 10.1038/s41388-026-03972-w
UR - https://doi.org/10.1038/s41388-026-03972-w
AB - The circadian rhythm is an intrinsic, self-regulatory physiological system in organisms that is hierarchically governed by core clock genes. Dysregulation of this rhythm is closely associated with tumor progression. However, the specific molecular mechanisms underlying circadian rhythm disruption–mediated colorectal cancer (CRC) remain largely elusive. The histone methyltransferase SET domain bifurcated 1 (SETDB1) exerts oncogenic functions in multiple solid tumors, prompting this study to investigate the molecular mechanisms through which SETDB1 regulates CRC progression. Our results demonstrate that SETDB1 acts as an oncogene in CRC by interacting with the Cullin 4B-RING E3 ligase (CRL4B) complex to enhance cancer cell proliferation, invasion, and stemness maintenance. Specifically, SETDB1 and the CRL4B complex assemble into a transcriptional repressor complex that binds to the promoters of core clock genes, such as PER3 and CRY1, to repress their transcription, thereby disrupting cellular circadian rhythms and ultimately accelerating CRC cell proliferation and metastasis. Collectively, our findings elucidate the pivotal role of the SETDB1/CRL4B complex in CRC pathogenesis and provide a potential therapeutic strategy targeting SETDB1 for patients with CRC with high CUL4B expression.
SN - 0950-9232
SN - 1476-5594
ER -