Upregulation of the transcription factor TFAP2D is associated with aggressive tumor phenotype in prostate cancer lacking the TMPRSS2:ERG fusion

Fraune, Christoph; Harms, Luisa; Büscheck, Franziska; Höflmayer, Doris; Clauditz, Till S.; Simon, Ronald; Möller, Katharina; Luebke, Andreas M.; Möller‐Koop, Christina; Steurer, Stefan; Hube‐Magg, Claudia; Sauter, Guido; Weidemann, Sören; Lebok, Patrick; Dum, David; Kind, Simon; Minner, Sarah; Izbicki, Jakob R.; Schlomm, Thorsten; Huland, Hartwig; Heinzer, Hans; Burandt, Eike; Haese, Alexander; Graefen, Markus; Schroeder, Cornelia

doi:10.1186/s10020-020-00148-4

Cited by 7 publications

(8 citation statements)

References 52 publications

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“…Recently, we examined the role of WWOX in conjunction with two interacting proteins, which together orchestrated biological processes diversely in BLCA depending on their cellular level [8]. These were two Activating Enhancer-Binding Protein 2 (AP-2) Transcription Factors (TFs), AP-2α and AP-2γ, members of the AP-2 family, whose natural function is related to early development regulation [9], but which are also involved in carcinogenesis [10][11][12][13][14], including BLCA [15][16][17]. AP-2α and AP-2γ have distinct roles in different tumors, and tend to play an anti-cancer or tumor-promoting role, respectively [9].…”

Section: Introductionmentioning

confidence: 99%

WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer

Kołat

Kałuzińska

Płuciennik

2021

Cancers

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The cytogenic locus of the WWOX gene overlaps with the second most active fragile site, FRA16D, which is present at a higher frequency in bladder cancer (BLCA) patients with smoking habit, a known risk factor of this tumor. Recently, we demonstrated the relevance of the role of WWOX in grade 2 BLCA in collaboration with two AP-2 transcription factors whose molecular actions supported or opposed pro-cancerous events, suggesting a distinct character. As further research is needed on higher grades, the aim of the present study was to examine WWOX-AP-2 functionality in grade 3 and 4 BLCA using equivalent in vitro methodology with additional transcriptome profiling of cellular variants. WWOX and AP-2α demonstrated similar anti-cancer functionality in most biological processes with subtle differences in MMP-2/9 regulation; this contradicted that of AP-2γ, whose actions potentiated cancer progression. Simultaneous overexpression of WWOX and AP-2α/AP-2γ revealed that single discrepancies appear in WWOX-AP-2α collaboration but only at the highest BLCA grade; WWOX-AP-2α collaboration was considered anti-cancer. However, WWOX only appeared to have residual activity against oncogenic AP-2γ in grade 3 and 4: variants with either AP-2γ overexpression alone or combined WWOX and AP-2γ overexpression demonstrated similar pro-tumoral behavior. Transcriptome profiling with further gene ontology certified biological processes investigated in vitro and indicated groups of genes consisting of AP-2 targets and molecules worth investigation as biomarkers. In conclusion, tumor suppressor synergism between WWOX and AP-2α is unimpaired in high-grade BLCA compared to intermediate grade, yet the ability of WWOX to guide oncogenic AP-2γ is almost completely lost.

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Section: Introductionmentioning

confidence: 99%

WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer

Kołat

Kałuzińska

Płuciennik

2021

Cancers

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“…In a significant fraction of PCa patients, CTCF showed high expression and was associated with tumor aggressiveness (high Gleason grade, advanced tumor stage, lymph node metastasis, early biochemical recurrence, as well as accelerated cell proliferation) (details are given in [ 45 ]). For TFAP2D, we observed that the TFAP2D level was high in about 75% of the patients with poorer clinical course, details see [ 44 ].…”

Section: Resultsmentioning

confidence: 99%

“…As reported recently, we identified the CCCTC-binding factor (CTCF) as a good prognostic marker specifically for patients with ERG-negative PCa [ 45 ]. IHC staining of TFAP2D (details, see [ 44 ]) and IRF1 showed that both transcription factors also suited as prognostic markers for PCa. For the predicted direct regulators MITF and BHLHE40, the immunohistochemical staining did not work in our assays.…”

Section: Discussionmentioning

confidence: 99%

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PITX1 Is a Regulator of TERT Expression in Prostate Cancer with Prognostic Power

Poos

Schroeder

Jaishankar

et al. 2022

Cancers

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The current risk stratification in prostate cancer (PCa) is frequently insufficient to adequately predict disease development and outcome. One hallmark of cancer is telomere maintenance. For telomere maintenance, PCa cells exclusively employ telomerase, making it essential for this cancer entity. However, TERT, the catalytic protein component of the reverse transcriptase telomerase, itself does not suit as a prognostic marker for prostate cancer as it is rather low expressed. We investigated if, instead of TERT, transcription factors regulating TERT may suit as prognostic markers. To identify transcription factors regulating TERT, we developed and applied a new gene regulatory modeling strategy to a comprehensive transcriptome dataset of 445 primary PCa. Six transcription factors were predicted as TERT regulators, and most prominently, the developmental morphogenic factor PITX1. PITX1 expression positively correlated with telomere staining intensity in PCa tumor samples. Functional assays and chromatin immune-precipitation showed that PITX1 activates TERT expression in PCa cells. Clinically, we observed that PITX1 is an excellent prognostic marker, as concluded from an analysis of more than 15,000 PCa samples. PITX1 expression in tumor samples associated with (i) increased Ki67 expression indicating increased tumor growth, (ii) a worse prognosis, and (iii) correlated with telomere length.

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“…Latest data regarding contribution in cancer indicates that AP-2β overexpression has been found to promote tumor growth in both breast and thyroid cancer and predicted poor prognosis or tumor progression, respectively [37,38]. Finally, although little is known of AP-2δ and AP-2ε, the former is thought to be associated with progression and genomic instability of prostate cancer while the latter acts as a tumor suppressor in neuroblastoma [39,40].…”

Section: Introductionmentioning

confidence: 99%

Functional genomics of AP-2α and AP-2γ in cancers: in silico study

et al. 2020

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Background Among all causes of death, cancer is the most prevalent and is only outpaced by cardiovascular diseases. Molecular theory of carcinogenesis states that apoptosis and proliferation are regulated by groups of tumor suppressors or oncogenes. Transcription factors are example of proteins comprising representatives of both cancer-related groups. Exemplary family of transcription factors which exhibits dualism of function is Activating enhancer-binding Protein 2 (AP-2). Scientific reports concerning their function in carcinogenesis depend on particular family member and/or tumor type which proves the issue to be unsolved. Therefore, the present study examines role of the best-described AP-2 representatives, AP-2α and AP-2γ, through ontological analysis of their target genes and investigation what processes are differentially regulated in 21 cancers using samples deposited in Genomic Data Analysis Center (GDAC) Firehose. Methods Expression data with clinical annotation was collected from TCGA-dedicated repository GDAC Firehose. Transcription factor targets were obtained from Gene Transcription Regulation Database (GTRD), TRANScription FACtor database (TRANSFAC) and Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRRUST). Monocle3 R package was used for global samples profiling while Protein ANalysis THrough Evolutionary Relationships (PANTHER) tool was used to perform gene ontology analysis. Results With RNA-seq data and Monocle3 or PANTHER tools we outlined differences in many processes and signaling pathways, separating tumor from normal tissues or tumors from each other. Unexpectedly, a number of alterations in basal-like breast cancer were identified that distinguished it from other subtypes, which could bring future clinical benefits. Conclusions Our findings indicate that while the AP-2α/γ role remains ambiguous, their activity is based on processes that underlie the cancer hallmarks and their expression could have potential in diagnosis of selected tumors.

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Upregulation of the transcription factor TFAP2D is associated with aggressive tumor phenotype in prostate cancer lacking the TMPRSS2:ERG fusion

Cited by 7 publications

References 52 publications

WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer

WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer

PITX1 Is a Regulator of TERT Expression in Prostate Cancer with Prognostic Power

Functional genomics of AP-2α and AP-2γ in cancers: in silico study

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