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Updated: May 16, 2026
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
Potential downstream target genes of aberrant ETS transcription factors are differentially affected in Ewing's
Maria J Camões1, Paula Paulo, Franclim R Ribeiro
1Department of Genetics, Portuguese Oncology Institute-Porto, Porto, Portugal.
Abstract:
FLI1 and ERG, the major ETS transcription factors involved in rearrangements in the Ewing's sarcoma family of tumors (ESFT) and in prostate carcinomas (PCa), respectively, belong to the same subfamily, having 98% sequence identity in the DNA binding domain. We therefore decided to investigate whether the aberrant transcription factors in both malignancies have some common downstream targets. We crossed a publicly available list of all putative EWSR1-FLI1 target genes in ESFT with our microarray expression data on 24 PCa and 6 non-malignant prostate tissues (NPT) and choose four genes among the top-most differentially expressed between PCa with (PCa ERG+) and without (PCa ETS-) ETS fusion genes (HIST1H4L, KCNN2, ECRG4 and LDOC1), as well as four well-validated direct targets of the EWSR1-FLI1 chimeric protein in ESFT (NR0B1, CAV1, IGFBP3 and TGFBR2). Using quantitative expression analysis in 16 ESFT and seven alveolar rhabdomyosarcomas (ARMS), we were able to validate the four genes previously described as direct targets of the EWSR1-FLI1 oncoprotein, showing overexpression of CAV1 and NR0B1 and underexpression of IGFBP3 and TGFBR2 in ESFT as compared to ARMS. Although none of these four genes showed significant expression differences between PCa ERG+ and PCa ETS-, CAV1, IGFBP3 and TGFBR2 were less expressed in PCa in an independent series of 56 PCa and 15 NPT, as also observed for ECRG4 and LDOC1, suggesting a role in prostate carcinogenesis in general. On the other hand, we demonstrate for the first time that both HIST1H4L and KCNN2 are significantly overexpressed in PCa ERG+ and that ERG binds to the promoter of these genes. Conversely, KCNN2 was found underexpressed in ESFT relative to ARMS, suggesting that the EWSR1-ETS oncoprotein may have the opposite effect of ERG rearrangements in PCa. We conclude that aberrant ETS transcription factors modulate target genes differently in ESFT and PCa.
Insights
Aberrant ETS transcription factors FLI1 and ERG have distinct downstream targets in Ewing sarcoma family tumors and prostate cancer. While some genes are commonly affected, others show cancer-specific regulation, impacting tumor development differently.
Area of Science:
- Molecular Biology
- Oncology
- Gene Regulation
Background:
- FLI1 and ERG are key ETS transcription factors implicated in Ewing's sarcoma family tumors (ESFT) and prostate carcinomas (PCa), respectively.
- These factors share high sequence identity in their DNA-binding domains, suggesting potential overlap in function and target genes.
- Understanding shared and distinct downstream targets is crucial for deciphering their roles in tumorigenesis.
Purpose of the Study:
- To investigate whether aberrant transcription factors FLI1 and ERG in ESFT and PCa, respectively, share common downstream target genes.
- To identify specific genes regulated by EWSR1-FLI1 in ESFT and ERG in PCa.
- To compare the regulatory effects of these ETS factors in different cancer types.
Main Methods:
- Cross-referencing EWSR1-FLI1 target genes in ESFT with microarray expression data from PCa and non-malignant prostate tissues (NPT).
- Quantitative expression analysis of selected candidate genes (HIST1H4L, KCNN2, ECRG4, LDOC1, NR0B1, CAV1, IGFBP3, TGFBR2) in ESFT, alveolar rhabdomyosarcomas (ARMS), and PCa.
- Chromatin immunoprecipitation (ChIP) or similar techniques to confirm ERG binding to gene promoters.
Main Results:
- Validated four previously identified direct EWSR1-FLI1 targets in ESFT, with differential expression of CAV1, NR0B1, IGFBP3, and TGFBR2 between ESFT and ARMS.
- Identified HIST1H4L and KCNN2 as novel, significantly overexpressed genes in ERG-positive PCa, with direct ERG promoter binding demonstrated for both.
- Observed underexpression of KCNN2 in ESFT relative to ARMS, suggesting opposing regulatory roles of EWSR1-FLI1 and ERG.
Conclusions:
- Aberrant ETS transcription factors FLI1 and ERG modulate distinct sets of target genes in ESFT and PCa.
- While some genes are commonly dysregulated (e.g., CAV1, IGFBP3, TGFBR2 in PCa), others are uniquely regulated, highlighting cancer-specific mechanisms.
- ERG directly binds to and upregulates HIST1H4L and KCNN2 in prostate cancer, whereas EWSR1-FLI1 may downregulate KCNN2 in ESFT.
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