Repression of transcription factor AP-2 alpha by PPARγ reveals a novel transcriptional circuit in basal-squamous bladder cancer

Yamashita, Haruo; Kawasawa, Yuka Imamura; Shuman, Lauren; Zheng, Zongyu; Tran, Tracy S.; Walter, Vonn; Warrick, Joshua I.; Chen, Guoli; Al‐Ahmadie, Hikmat; Kaag, Matthew; Wong, Pak Kin; Raman, Jay D.; DeGraff, David J.

doi:10.1038/s41389-019-0178-3

Cited by 27 publications

(39 citation statements)

References 42 publications

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“…Our results show that the epigenetic regulation is a key contributor to molecular subtype assignment in both commonly used models of BLCA and in patient-tumors. [32] and TFAP2C [16] were previously reported to be a luminal and basal-squamous-specific genes, respectively, thereby validating our findings. Interestingly, binding motifs for AP-1 complex proteins FOXA1 and GATA3 are known to play a role in the development of urothelium [32] suggesting that their binding sites may be primed early during development.…”

Section: Luminal and Basal Blca Subtypes Are Regulated By Distinct Epsupporting

confidence: 91%

“…Recent studies have identified both luminal (FOXA1, GATA3 and PPARG [8]) and basal (TP63 [9][10][11][12], STAT3 [4,[13][14][15], TFAP2A and TFAP2C [16]) -specific transcription factors (TFs) with functional roles in BLCA. For instance, we previously reported that FOXA1 and GATA3 cooperates with PPARG activation to drive trans-differentiation of basal BLCA cells to luminal subtype [8].…”

Section: Introductionmentioning

confidence: 99%

“…Subtype-specific TFs also appear to drive programs in oncogenesis and tumor progression. For example, basal factors STAT3, TP63 and TFAP2A/C have shown to promote tumor cell invasion and/or metastasis [12,13,16]. Similarly loss of FOXA1 [19] and GATA3 [20] have been shown to promote cell migration and invasion.…”

Section: Introductionmentioning

confidence: 99%

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Subtype-specific epigenomic landscape and 3D genome structure in bladder cancer

Iyyanki

Zhang

Jin

et al. 2020

Preprint

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Muscle-invasive bladder cancers have recently been characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. For example, FOXA1, GATA3, and PPARG have been shown to be essential for luminal subtype-specific regulation and subtype switching, while TP63 and STAT3 are critical for basal subtype bladder cancer. Despite these advances, the underlying epigenetic mechanism and 3D chromatin architecture for subtypespecific regulation in bladder cancers remains largely unknown. Here, we determined the genome-wide transcriptome, enhancer landscape, TF binding profiles (FOXA1 and GATA3) in luminal and basal subtypes of bladder cancers. Furthermore, we mapped genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors, for the first time in bladder cancer. We showed that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct TF binding at distal-enhancers of luminal and basal bladder cancers. Finally, we identified a novel clinically relevant transcriptional factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other luminal-specific genes (such as FOXA1, GATA3, and PPARG) and affects cancer cell proliferation and migration. In summary, our work shows a subtype-specific epigenomic and 3D genome structure in urinary bladder cancers and suggested a novel link between the circadian TF NPAS2 and a clinical bladder cancer subtype.

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Section: Luminal and Basal Blca Subtypes Are Regulated By Distinct Epsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Subtype-specific epigenomic landscape and 3D genome structure in bladder cancer

Iyyanki

Zhang

Jin

et al. 2020

Preprint

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“…The molecular mechanism driving a tumor towards a basal/squamous subtype is currently unknown. In a recent study, Yamashita et al [20] show that Transcription Factor Activating Protein 2 alpha (TFAP2A) is expressed at high levels in basal-squamous bladder cancer, enriched in areas of squamous differentiation, and is associated with increase lymph node metastasis and distant recurrence of the disease. The study also shows that increased expression of TFAP2A can facilitate the expression of other transcription factors such as tumor protein p63 (TP63/P63) also known as p63, which is known to be associated with the basal subtype of UC [21].…”

Section: Introductionmentioning

confidence: 99%

“…The luminal subtype of UC is associated with the expression of the transcriptional factors forkhead box protein A1 (FOXA1), GATA binding protein 3 (GATA3) and peroxisome proliferator-activated receptor gamma (PPARγ) [23,24]. The activation of PPARγ with an agonist can represses the expression of TFAP2A [20] and inhibit squamous differentiation in vitro [25].…”

Section: Introductionmentioning

confidence: 99%

Activation of PPARγ and inhibition of cell proliferation reduces key proteins associated with the basal subtype of bladder cancer in As3+-transformed UROtsa cells

et al. 2020

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Environmental exposure to arsenite (As 3+) has a strong association with the development of human urothelial cancer (UC) and is the 5 th most common cancer in men and the 12 th most common cancer in women. Muscle invasive urothelial cancer (MIUC) are grouped into basal or luminal molecular subtypes based on their gene expression profile. The basal subtype is more aggressive and can be associated with squamous differentiation, characterized by high expression of keratins (KRT1, 5, 6, 14, and 16) and epidermal growth factor receptor (EGFR) within the tumors. The luminal subtype is less aggressive and is predominately characterized by elevated gene expression of peroxisome proliferator-activated receptorgamma (PPARγ) and forkhead box protein A1 (FOXA1). We have previously shown that As 3+-transformed urothelial cells (As-T) exhibit a basal subtype of UC expressing genes associated with squamous differentiation. We hypothesized that the molecular subtype of the As-T cells could be altered by inducing the expression of PPARγ and/or inhibiting the proliferation of the cells. Non-transformed and As-T cells were treated with Troglitazone (TG, PPARG agonist, 10 μM), PD153035 (PD, an EGFR inhibitor, 1 μM) or a combination of TG and PD for 3 days. The results obtained demonstrate that treatment of the As-T cells with TG upregulated the expression of PPARγ and FOXA1 whereas treatment with PD decreased the expression of some of the basal keratins. However, a combined treatment of TG and PD resulted in a consistent decrease of several proteins associated with the basal subtype of bladder cancers (KRT1, KRT14, KRT16, P63, and TFAP2A). Our data suggests that activation of PPARγ while inhibiting cell proliferation facilitates the regulation of genes involved in maintaining the luminal subtype of UC. In vivo animal studies are needed to address the efficacy of using PPARγ agonists and/or proliferation inhibitors to reduce tumor grade/stage of MIUC.

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Molecular profile of pure squamous cell carcinoma of the bladder identifies major roles for OSMR and YAP signalling

Hurst

Guo

Platt

et al. 2022

The Journal of Pathology CR

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Pure squamous cell carcinoma (SCC) is the most common pure variant form of bladder cancer, found in 2-5% of cases. It often presents late and is unresponsive to cisplatin-based chemotherapy. The molecular features of these tumours have not been elucidated in detail. We carried out whole-exome sequencing (WES), copy number, and transcriptome analysis of bladder SCC. Muscle-invasive bladder cancer (MIBC) samples with no evidence of squamous differentiation (non-SD) were used for comparison. To assess commonality of features with urothelial carcinoma with SD, we examined data from SD samples in The Cancer Genome Atlas (TCGA) study of MIBC. TP53 was the most commonly mutated gene in SCC (64%) followed by FAT1 (45%). Copy number analysis revealed complex changes in SCC, many differing from those in samples with SD. Gain of 5p and 7p was the most common feature, and focal regions on 5p included OSMR and RICTOR. In addition to 9p deletions, we found some samples with focal gain of 9p24 containing CD274 (PD-L1). Loss of 4q35 containing FAT1 was found in many samples such that all but one sample analysed by WES had FAT1 mutation or deletion. Expression features included upregulation of oncostatin M receptor (OSMR), metalloproteinases, metallothioneins, keratinisation genes, extracellular matrix components, inflammatory response genes, stem cell markers, and immune response modulators. Exploration of differentially expressed transcription factors identified BNC1 and TFAP2A, a gene repressed by PPARG, as the most upregulated factors. Known urothelial differentiation factors were downregulated along with 72 Kruppel-associated (KRAB) domain-containing zinc finger family protein (KZFP) genes. Novel therapies are urgently needed for these tumours. In addition to upregulated expression of EGFR, which has been suggested as a therapeutic target in basal/squamous bladder cancer, we identified expression signatures that indicate upregulated OSMR and YAP/TAZ signalling. Preclinical evaluation of the effects of inhibition of these pathways alone or in combination is merited.

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Repression of transcription factor AP-2 alpha by PPARγ reveals a novel transcriptional circuit in basal-squamous bladder cancer

Cited by 27 publications

References 42 publications

Subtype-specific epigenomic landscape and 3D genome structure in bladder cancer

Subtype-specific epigenomic landscape and 3D genome structure in bladder cancer

Activation of PPARγ and inhibition of cell proliferation reduces key proteins associated with the basal subtype of bladder cancer in As3+-transformed UROtsa cells

Molecular profile of pure squamous cell carcinoma of the bladder identifies major roles for OSMR and YAP signalling

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