Epigenetic regulator BMI1 promotes fusion-positive rhabdomyosarcoma proliferation and constitutes a novel therapeutic target
ABSTRACT Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma that continues to present significant challenges to pediatric oncology. There are two major subtypes of pediatric rhabdomyosarcoma, alveolar and embryonal. Alveolar rhabdomyosarcomas are characterized by the presence of a PAX-FOXO1 fusion protein and termed fusion-positive (FP-RMS); embryonal rhabdomyosarcomas (ERMS) lack these fusions and are termed fusion-negative (FN-RMS).Fusion-positive rhabdomyosarcoma (FP-RMS) harbors PAX-FOXO1 fusion proteins and has a worse overall outcome compared to FN-RMS, underscoring the critical need to identify novel targets for this disease. While fusion proteins remain challenging therapeutic targets, recent studies have begun to reveal the key intersection of PAX-FOXO1 fusion proteins with the malignant epigenome, suggesting that epigenetic proteins may serve as novel targets in FP-RMS. Here, we investigate the contribution of the epigenetic regulator BMI1 to FP-RMS.We examined RNA-seq tumor datasets and determined thatBMI1is robustly expressed in FP-RMS tumors, patient derived xenografts (PDXs), and cell lines. We depleted BMI1 using RNA interference and find that this leads to a marked decrease in cell growth. Next, we used two BMI1 inhibitors, PTC-209 and PTC-028, and showed that BMI1 inhibition decreases cell cycle progression and increases apoptosis in FP-RMS cell lines. In thein vivosetting, targeting BMI1 leads to decreased tumor growth. Mechanistically, we observe that BMI1 inhibition activates the tumor suppressive Hippo pathway. Collectively, these results identify BMI1 as a novel therapeutic vulnerability in FP-RMS and provide a foundation for further investigation of BMI1 in both FP-RMS and additional sarcoma histotypes..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 21. Okt. Zur Gesamtaufnahme - year:2022 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Shields, Cara E. [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| doi: |
10.1101/2020.04.18.048355 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI017602904 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI017602904 | ||
| 003 | DE-627 | ||
| 005 | 20230429075649.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 200420s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2020.04.18.048355 |2 doi | |
| 035 | |a (DE-627)XBI017602904 | ||
| 035 | |a (biorXiv)10.1101/2020.04.18.048355 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Shields, Cara E. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Epigenetic regulator BMI1 promotes fusion-positive rhabdomyosarcoma proliferation and constitutes a novel therapeutic target |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a ABSTRACT Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma that continues to present significant challenges to pediatric oncology. There are two major subtypes of pediatric rhabdomyosarcoma, alveolar and embryonal. Alveolar rhabdomyosarcomas are characterized by the presence of a PAX-FOXO1 fusion protein and termed fusion-positive (FP-RMS); embryonal rhabdomyosarcomas (ERMS) lack these fusions and are termed fusion-negative (FN-RMS).Fusion-positive rhabdomyosarcoma (FP-RMS) harbors PAX-FOXO1 fusion proteins and has a worse overall outcome compared to FN-RMS, underscoring the critical need to identify novel targets for this disease. While fusion proteins remain challenging therapeutic targets, recent studies have begun to reveal the key intersection of PAX-FOXO1 fusion proteins with the malignant epigenome, suggesting that epigenetic proteins may serve as novel targets in FP-RMS. Here, we investigate the contribution of the epigenetic regulator BMI1 to FP-RMS.We examined RNA-seq tumor datasets and determined thatBMI1is robustly expressed in FP-RMS tumors, patient derived xenografts (PDXs), and cell lines. We depleted BMI1 using RNA interference and find that this leads to a marked decrease in cell growth. Next, we used two BMI1 inhibitors, PTC-209 and PTC-028, and showed that BMI1 inhibition decreases cell cycle progression and increases apoptosis in FP-RMS cell lines. In thein vivosetting, targeting BMI1 leads to decreased tumor growth. Mechanistically, we observe that BMI1 inhibition activates the tumor suppressive Hippo pathway. Collectively, these results identify BMI1 as a novel therapeutic vulnerability in FP-RMS and provide a foundation for further investigation of BMI1 in both FP-RMS and additional sarcoma histotypes. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Potlapalli, Sindhu |e verfasserin |4 aut | |
| 700 | 1 | |a Cuya-Smith, Selma M. |e verfasserin |4 aut | |
| 700 | 1 | |a Chappell, Sarah K. |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Dongdong |e verfasserin |4 aut | |
| 700 | 1 | |a Martinez, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Pogoriler, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Rathi, Komal S. |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Shiv A. |e verfasserin |4 aut | |
| 700 | 1 | |a Maris, John M. |e verfasserin |4 aut | |
| 700 | 1 | |a Schnepp, Robert W. |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2022) vom: 21. Okt. |
| 773 | 1 | 8 | |g year:2022 |g day:21 |g month:10 |
| 856 | 4 | 0 | |u https://doi.org/10.1002/1878-0261.12914 |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2020.04.18.048355 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 912 | |a SSG-OLC-PHA | ||
| 951 | |a AR | ||
| 952 | |j 2022 |b 21 |c 10 | ||