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

Hironobu Yamashita, Yuka I. Kawasawa, Lauren Shuman, Zongyu Zheng, Truc Tran, Vonn Walter, Joshua I. Warrick, Guoli Chen, Hikmat Al-Ahmadie, Matthew Kaag, Pak Kin Wong, Jay D. Raman, David J. DeGraff

Research output: Contribution to journalArticle

Abstract

The discovery of bladder cancer transcriptional subtypes provides an opportunity to identify high risk patients, and tailor disease management. Recent studies suggest tumor heterogeneity contributes to regional differences in molecular subtype within the tumor, as well as during progression and following treatment. Nonetheless, the transcriptional drivers of the aggressive basal-squamous subtype remain unidentified. As PPARɣ has been repeatedly implicated in the luminal subtype of bladder cancer, we hypothesized inactivation of this transcriptional master regulator during progression results in increased expression of basal-squamous specific transcription factors (TFs) which act to drive aggressive behavior. We initiated a pharmacologic and RNA-seq-based screen to identify PPARɣ-repressed, basal-squamous specific TFs. Hierarchical clustering of RNA-seq data following treatment of three human bladder cancer cells with a PPARɣ agonist identified a number of TFs regulated by PPARɣ activation, several of which are implicated in urothelial and squamous differentiation. One PPARɣ-repressed TF implicated in squamous differentiation identified is Transcription Factor Activating Protein 2 alpha (TFAP2A). We show TFAP2A and its paralog TFAP2C are overexpressed in basal-squamous bladder cancer and in squamous areas of cystectomy samples, and that overexpression is associated with increased lymph node metastasis and distant recurrence, respectively. Biochemical analysis confirmed the ability of PPARɣ activation to repress TFAP2A, while PPARɣ antagonist and PPARɣ siRNA knockdown studies indicate the requirement of a functional receptor. In vivo tissue recombination studies show TFAP2A and TFAP2C promote tumor growth in line with the aggressive nature of basal-squamous bladder cancer. Our findings suggest PPARɣ inactivation, as well as TFAP2A and TFAP2C overexpression cooperate with other TFs to promote the basal-squamous transition during tumor progression.

Original languageEnglish (US)
Article number69
JournalOncogenesis
Volume8
Issue number12
DOIs
StatePublished - Dec 1 2019

Fingerprint

Transcription Factor AP-2
PPAR alpha
Peroxisome Proliferator-Activated Receptors
Activating Transcription Factor 2
Urinary Bladder Neoplasms
Transcription Factors
Proteins
Neoplasms
RNA
Aptitude
Cystectomy
Disease Management
Small Interfering RNA
Genetic Recombination
Cluster Analysis
Lymph Nodes
Neoplasm Metastasis
Recurrence

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

Cite this

Yamashita, Hironobu ; Kawasawa, Yuka I. ; Shuman, Lauren ; Zheng, Zongyu ; Tran, Truc ; Walter, Vonn ; Warrick, Joshua I. ; Chen, Guoli ; Al-Ahmadie, Hikmat ; Kaag, Matthew ; Wong, Pak Kin ; Raman, Jay D. ; DeGraff, David J. / Repression of transcription factor AP-2 alpha by PPARγ reveals a novel transcriptional circuit in basal-squamous bladder cancer. In: Oncogenesis. 2019 ; Vol. 8, No. 12.
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abstract = "The discovery of bladder cancer transcriptional subtypes provides an opportunity to identify high risk patients, and tailor disease management. Recent studies suggest tumor heterogeneity contributes to regional differences in molecular subtype within the tumor, as well as during progression and following treatment. Nonetheless, the transcriptional drivers of the aggressive basal-squamous subtype remain unidentified. As PPARɣ has been repeatedly implicated in the luminal subtype of bladder cancer, we hypothesized inactivation of this transcriptional master regulator during progression results in increased expression of basal-squamous specific transcription factors (TFs) which act to drive aggressive behavior. We initiated a pharmacologic and RNA-seq-based screen to identify PPARɣ-repressed, basal-squamous specific TFs. Hierarchical clustering of RNA-seq data following treatment of three human bladder cancer cells with a PPARɣ agonist identified a number of TFs regulated by PPARɣ activation, several of which are implicated in urothelial and squamous differentiation. One PPARɣ-repressed TF implicated in squamous differentiation identified is Transcription Factor Activating Protein 2 alpha (TFAP2A). We show TFAP2A and its paralog TFAP2C are overexpressed in basal-squamous bladder cancer and in squamous areas of cystectomy samples, and that overexpression is associated with increased lymph node metastasis and distant recurrence, respectively. Biochemical analysis confirmed the ability of PPARɣ activation to repress TFAP2A, while PPARɣ antagonist and PPARɣ siRNA knockdown studies indicate the requirement of a functional receptor. In vivo tissue recombination studies show TFAP2A and TFAP2C promote tumor growth in line with the aggressive nature of basal-squamous bladder cancer. Our findings suggest PPARɣ inactivation, as well as TFAP2A and TFAP2C overexpression cooperate with other TFs to promote the basal-squamous transition during tumor progression.",
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Repression of transcription factor AP-2 alpha by PPARγ reveals a novel transcriptional circuit in basal-squamous bladder cancer. / Yamashita, Hironobu; Kawasawa, Yuka I.; Shuman, Lauren; Zheng, Zongyu; Tran, Truc; Walter, Vonn; Warrick, Joshua I.; Chen, Guoli; Al-Ahmadie, Hikmat; Kaag, Matthew; Wong, Pak Kin; Raman, Jay D.; DeGraff, David J.

In: Oncogenesis, Vol. 8, No. 12, 69, 01.12.2019.

Research output: Contribution to journalArticle

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AU - Yamashita, Hironobu

AU - Kawasawa, Yuka I.

AU - Shuman, Lauren

AU - Zheng, Zongyu

AU - Tran, Truc

AU - Walter, Vonn

AU - Warrick, Joshua I.

AU - Chen, Guoli

AU - Al-Ahmadie, Hikmat

AU - Kaag, Matthew

AU - Wong, Pak Kin

AU - Raman, Jay D.

AU - DeGraff, David J.

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