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Doxorubicin induces prolonged DNA damage signal in cells overexpressing DEK isoform-2
Emrah Özçelik1, Ahmet Kalaycı1, Büşra Çelik1
1Department of Molecular Biology and Genetics, Gebze Technical University, Gebze, Kocaeli, Turkey.
Abstract:
DEK has a short isoform (DEK isoform-2; DEK2) that lacks amino acid residues between 49-82. The full-length DEK (DEK isoform-1; DEK1) is ubiquitously expressed and plays a role in different cellular processes but whether DEK2 is involved in these processes remains elusive. We stably overexpressed DEK2 in human bone marrow stromal cell line HS-27A, in which endogenous DEKs were intact or suppressed via short hairpin RNA (sh-RNA). We have found that contrary to ectopic DEK1, DEK2 locates in the nucleus and nucleolus, causes persistent γH2AX signal upon doxorubicin treatment, and couldn't functionally compensate for the loss of DEK1. In addition, DEK2 overexpressing cells were more sensitive to doxorubicin than DEK1-cells. Expressions of DEK1 and DEK2 in cell lines and primary tumors exhibit tissue specificity. DEK1 is upregulated in cancers of the colon, liver, and lung compared to normal tissues while both DEK1 and DEK2 are downregulated in subsets of kidney, prostate, and thyroid carcinomas. Interestingly, only DEK2 was downregulated in a subset of breast tumors suggesting that DEK2 can be modulated differently than DEK1 in specific cancers. In summary, our findings show distinct expression patterns and subcellular location and suggest non-overlapping functions between the two DEK isoforms.
Insights
The DEK proto-oncogene has two isoforms, DEK1 and DEK2. DEK2, unlike DEK1, localizes to the nucleus and nucleolus, and does not compensate for DEK1 loss, suggesting distinct functions.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The DEK proto-oncogene exists in full-length (DEK1) and short (DEK2) isoforms.
- DEK1 is ubiquitously expressed and involved in cellular processes, but DEK2's role is unclear.
- Understanding DEK isoform function is crucial for cancer biology.
Purpose of the Study:
- To investigate the distinct cellular localization, function, and expression patterns of DEK1 and DEK2.
- To determine if DEK2 can functionally compensate for DEK1.
- To analyze the differential expression of DEK isoforms in various human cancers.
Main Methods:
- Stable overexpression of DEK2 in HS-27A cells.
- Short hairpin RNA (sh-RNA) mediated suppression of endogenous DEKs.
- Doxorubicin treatment to assess cellular response and DNA damage (γH2AX).
- Analysis of DEK1 and DEK2 expression in cell lines and primary tumor tissues.
Main Results:
- DEK2 localized to the nucleus and nucleolus, distinct from DEK1.
- DEK2 did not compensate for DEK1 loss and increased sensitivity to doxorubicin.
- DEK1 and DEK2 expression showed tissue specificity.
- DEK1 was upregulated in colon, liver, and lung cancers; both were downregulated in kidney, prostate, and thyroid cancers.
- DEK2, but not DEK1, was downregulated in a subset of breast tumors.
Conclusions:
- DEK1 and DEK2 possess distinct subcellular localizations and non-overlapping functions.
- DEK2's unique expression pattern suggests specific roles in certain cancer types.
- Differential modulation of DEK isoforms highlights their complex involvement in tumorigenesis.
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