Interaction of transcription factor AP‐2 gamma with proto‐oncogene PELP1 promotes tumorigenesis by enhancing RET signaling

Liu, Junhao; Liu, Zexuan; Li, Mengxing; Tang, Weiwei; Pratap, Uday P.; Luo, Yiliao; Altwegg, Kristin A.; Li, Xiaonan; Zou, Yi; Zhu, Hong; Sareddy, Gangadhara R.; Viswanadhapalli, Suryavathi; Vadlamudi, Ratna K.

doi:10.1002/1878-0261.12871

Cited by 14 publications

(11 citation statements)

References 41 publications

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“…This is not only manifested in apoptosis assay disputed above but can be confirmed by literature data investigating colony formation in cervical cancer (23), myeloma (64) and leukemia (63). Assumption of superiority of such mechanism over AP-2g ability to increase clonogenicity via interaction with Proline-, Glutamate-and Leucine-rich Protein 1 (PELP1) to enhance REarranged during Transfection (RET) signaling (65) is probably one of few explanations yet it fits our study findings. Conclusiveness is also limited due to lack of data regarding PELP1 in bladder cancer but assuming negative correlation between PELP1 and miR-200 family (66) and the fact that these miRNAs are directly repressed by Twist-related protein 1 (TWIST1) in bladder cancer (67) whose expression decreases with the PELP1 knockdown (68), we can assume that its role is not without significance.…”

Section: Discussionsupporting

confidence: 89%

Fragile Gene WWOX Guides TFAP2A/TFAP2C-Dependent Actions Against Tumor Progression in Grade II Bladder Cancer

2021

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IntroductionThe presence of common fragile sites is associated with no-accidental chromosomal instability which occurs prior to carcinogenesis. The WWOX gene spans the second most active fragile site: FRA16D. Chromosomal breakage at this site is more common in bladder cancer patients who are tobacco smokers which suggests the importance of WWOX gene loss regarding bladder carcinogenesis. Tryptophan domains of WWOX are known to recognize motifs of other proteins such as AP-2α and AP-2γ allowing protein-protein interactions. While the roles of both AP-2 transcription factors are important for bladder carcinogenesis, their nature is different. Based on the literature, AP-2γ appears to be oncogenic, whereas AP-2α mainly exhibits tumor suppressor character. Presumably, the interaction between WWOX and both transcription factors regulates thousands of genes, hence the aim of the present study was to determine WWOX, AP-2α, and AP-2γ function in modulating biological processes of bladder cancer.MethodsRT-112 cell line (grade II bladder cancer) was subjected to two stable lentiviral transductions. Overall, this resulted in six variants to investigate distinct WWOX, AP-2α, or AP-2γ function as well as WWOX in collaboration with a particular transcription factor. Cellular models were examined with immunocytochemical staining and in terms of differences in biological processes using assays investigating cell viability, proliferation, apoptosis, adhesion, clonogenicity, migration, activity of metalloproteinases and 3D culture growth.ResultsWWOX overexpression increased apoptosis but decreased cell viability, migration and large spatial colonies. AP-2α overexpression decreased tumor cell viability, migratory potential, matrix metalloproteinase-2 activity and clonogenicity. AP-2γ overexpression decreased matrix metalloproteinase-2 activity but increased wound healing, adhesion, clonogenicity and spatial colony formation. WWOX and AP-2α overexpression induced apoptosis but decreased cell viability, adhesion, matrix metalloproteinase-2 activity, overall number of cultured colonies and migration rate. WWOX and AP-2γ overexpression decreased tumor cell viability, proliferation potential, adhesion, clonogenicity and the ability to create spatial structures, but also increased apoptosis or migration rate.ConclusionCo-overexpression of WWOX with AP-2α or WWOX with AP-2γ resulted in a net anti-tumor effect. However, considering this research findings and the difference between AP-2α and AP-2γ, we suggest that this similarity is due to a divergent behavior of WWOX.

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Section: Discussionsupporting

confidence: 89%

Fragile Gene WWOX Guides TFAP2A/TFAP2C-Dependent Actions Against Tumor Progression in Grade II Bladder Cancer

2021

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“…Regarding AP-2γ, its individ-ual overexpression (K/C) increased the number of colonies of both cell lines, but when combined with WWOX (W/C), it only appeared to do so in G3 BLCA. This oncogene can increase colony formation due to enhancement of RET signaling via interaction with PELP1 [68].…”

Section: Discussionmentioning

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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“…Alterations in the coregulator expression or functions enable ERα-signaling from AE-ER complexes, essentially converting the antagonist to an agonist [88,89]. Approximately, 38% of ESR1 coregulators identified in BC are over-expressed [87,90,91], such as SRC3 [92,93], SRC2 [94], and PELP1 [95]. These deregulated coregulators contribute to BC progression [91], therapy resistance, and metastases [96][97][98][99].…”

Section: Coregulators and Endocrine Therapy Resistancementioning

confidence: 99%

“…Approximately, 38% of ESR1 coregulators identified in BC are over-expressed [87,90,91], such as SRC3 [92,93], SRC2 [94], and PELP1 [95]. These deregulated coregulators contribute to BC progression [91], therapy resistance, and metastases [96][97][98][99]. The zeste homolog (EZH) 2-mediates epigenetic silencing of ERα cofactor growth regulation by estrogen in BC 1 (GREB1) contributes to the development of tamoxifen resistance [100].…”

Section: Coregulators and Endocrine Therapy Resistancementioning

confidence: 99%

Role of estrogen receptor coregulators in endocrine resistant breast cancer

Altwegg

Vadlamudi

2021

Exploration of Targeted Anti-Tumor Therapy

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Breast cancer (BC) is the most ubiquitous cancer in women. Approximately 70-80% of BC diagnoses are positive for estrogen receptor (ER) alpha (ERα). The steroid hormone estrogen [17β-estradiol (E2)] plays a vital role both in the initiation and progression of BC. The E2-ERα mediated actions involve genomic signaling and non-genomic signaling. The specificity and magnitude of ERα signaling are mediated by interactions between ERα and several coregulator proteins called coactivators or corepressors. Alterations in the levels of coregulators are common during BC progression and they enhance ligand-dependent and ligand-independent ERα signaling which drives BC growth, progression, and endocrine therapy resistance. Many ERα coregulator proteins function as scaffolding proteins and some have intrinsic or associated enzymatic activities, thus the targeting of coregulators for blocking BC progression is a challenging task. Emerging data from in vitro and in vivo studies suggest that targeting coregulators to inhibit BC progression to therapy resistance is feasible. This review explores the current state of ERα coregulator signaling and the utility of targeting the ERα coregulator axis in treating advanced BC.

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Interaction of transcription factor AP‐2 gamma with proto‐oncogene PELP1 promotes tumorigenesis by enhancing RET signaling

Cited by 14 publications

References 41 publications

Fragile Gene WWOX Guides TFAP2A/TFAP2C-Dependent Actions Against Tumor Progression in Grade II Bladder Cancer

Fragile Gene WWOX Guides TFAP2A/TFAP2C-Dependent Actions Against Tumor Progression in Grade II Bladder Cancer

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

Role of estrogen receptor coregulators in endocrine resistant breast cancer

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