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Transcriptional mod...
Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells
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- Ali, Muhammad Akhtar (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi
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- Younis, Shady (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinsk biokemi och mikrobiologi
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- Wallerman, Ola (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för husdjursgenetik (HGEN),Department of Animal Breeding and Genetics
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- Gupta, Rajesh (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Vaskulärbiologi
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- Andersson, Leif (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinsk biokemi och mikrobiologi,Institutionen för husdjursgenetik (HGEN),Department of Animal Breeding and Genetics,Uppsala University,Texas A&M University
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- Sjoblöm, Tobias (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi
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(creator_code:org_t)
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- 2015-06-08
- 2015
- English.
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:25, s. 7743-7748
- Related links:
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https://doi.org/10.1...
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https://www.pnas.org...
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https://urn.kb.se/re...
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https://res.slu.se/i...
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Abstract
Subject headings
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- The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-beta, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.
Subject headings
- NATURVETENSKAP -- Biologi -- Genetik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Genetics (hsv//eng)
- NATURVETENSKAP -- Biologi -- Cellbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Cell Biology (hsv//eng)
Keyword
- ZBED6
- colorectal cancer
- IGF2
- PI3K pathway
Publication and Content Type
- ref (subject category)
- art (subject category)
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