Cell-Intrinsic Tumorigenic Functions of PPARγ in Bladder Urothelial Carcinoma
©2021 American Association for Cancer Research..
The role of PPAR gamma (PPARγ) has been well characterized in the developmental process of adipogenesis, yet its aberrant expression patterns and functions in cancer subtypes are less understood. Although PPARγ has been recently demonstrated to play non-cell-autonomous roles in promoting bladder urothelial carcinoma (UC) progression, underlying mechanisms of the cell-intrinsic oncogenic activity remain unknown. Here, we report robust expression and nuclear accumulation of PPARγ in 47% of samples of patients with UC, exceeding mRNA expression patterns published by The Cancer Genome Atlas. In vitro assays revealed for the first time that treatment of UC cells with PPARγ inverse agonist or PPARG knockout by CRISPR-Cas9 reduces proliferation, migration, and invasion of multiple established UC cell lines, most strongly in those characterized by PPARG genomic amplification or activating mutations of RXRA, the obligate heterodimer of PPARγ. Through genome-wide approaches including chromatin immunoprecipitation sequencing and RNA sequencing, we define a novel set of PPARγ-regulated genes in UC, including Sonic Hedgehog (SHH). Similar to PPARγ, genetic inhibition of SHH reduces proliferation and motility. Finally, we demonstrate the PPARγ dependency of UC tumors in vivo by genetic and pharmacologic PPARγ inhibition in subcutaneous xenografts. Collectively, our data indicate that PPARγ promotes UC progression in a subset of patients, at least in part, through cell-autonomous mechanisms linked to SHH signaling. IMPLICATIONS: Genome-wide analysis of DNA-binding sites for oncogenic factor PPARγ revealed SHH as a novel downstream target involved in UC progression, providing important insight into the tumorigenic nature and molecular mechanism of PPARγ signaling in UC.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
|---|---|
| Enthalten in: |
Molecular cancer research : MCR - 19(2021), 4 vom: 11. Apr., Seite 598-611 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Sanchez, Danielle J [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Benzamides |
|---|
| Anmerkungen: |
Date Completed 12.01.2022 Date Revised 05.10.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1158/1541-7786.MCR-20-0189 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM319950352 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM319950352 | ||
| 003 | DE-627 | ||
| 005 | 20231225172536.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1158/1541-7786.MCR-20-0189 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1066.xml |
| 035 | |a (DE-627)NLM319950352 | ||
| 035 | |a (NLM)33431608 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Sanchez, Danielle J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Cell-Intrinsic Tumorigenic Functions of PPARγ in Bladder Urothelial Carcinoma |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 12.01.2022 | ||
| 500 | |a Date Revised 05.10.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2021 American Association for Cancer Research. | ||
| 520 | |a The role of PPAR gamma (PPARγ) has been well characterized in the developmental process of adipogenesis, yet its aberrant expression patterns and functions in cancer subtypes are less understood. Although PPARγ has been recently demonstrated to play non-cell-autonomous roles in promoting bladder urothelial carcinoma (UC) progression, underlying mechanisms of the cell-intrinsic oncogenic activity remain unknown. Here, we report robust expression and nuclear accumulation of PPARγ in 47% of samples of patients with UC, exceeding mRNA expression patterns published by The Cancer Genome Atlas. In vitro assays revealed for the first time that treatment of UC cells with PPARγ inverse agonist or PPARG knockout by CRISPR-Cas9 reduces proliferation, migration, and invasion of multiple established UC cell lines, most strongly in those characterized by PPARG genomic amplification or activating mutations of RXRA, the obligate heterodimer of PPARγ. Through genome-wide approaches including chromatin immunoprecipitation sequencing and RNA sequencing, we define a novel set of PPARγ-regulated genes in UC, including Sonic Hedgehog (SHH). Similar to PPARγ, genetic inhibition of SHH reduces proliferation and motility. Finally, we demonstrate the PPARγ dependency of UC tumors in vivo by genetic and pharmacologic PPARγ inhibition in subcutaneous xenografts. Collectively, our data indicate that PPARγ promotes UC progression in a subset of patients, at least in part, through cell-autonomous mechanisms linked to SHH signaling. IMPLICATIONS: Genome-wide analysis of DNA-binding sites for oncogenic factor PPARγ revealed SHH as a novel downstream target involved in UC progression, providing important insight into the tumorigenic nature and molecular mechanism of PPARγ signaling in UC | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Benzamides |2 NLM | |
| 650 | 7 | |a PPAR gamma |2 NLM | |
| 650 | 7 | |a PPARG protein, human |2 NLM | |
| 650 | 7 | |a Pyridines |2 NLM | |
| 650 | 7 | |a T 0070907 |2 NLM | |
| 700 | 1 | |a Missiaen, Rindert |e verfasserin |4 aut | |
| 700 | 1 | |a Skuli, Nicolas |e verfasserin |4 aut | |
| 700 | 1 | |a Steger, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Simon, M Celeste |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Molecular cancer research : MCR |d 2002 |g 19(2021), 4 vom: 11. Apr., Seite 598-611 |w (DE-627)NLM122798910 |x 1557-3125 |7 nnns |
| 773 | 1 | 8 | |g volume:19 |g year:2021 |g number:4 |g day:11 |g month:04 |g pages:598-611 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1158/1541-7786.MCR-20-0189 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 19 |j 2021 |e 4 |b 11 |c 04 |h 598-611 | ||