UHRF1 downmodulation enhances antitumor effects of histone deacetylase inhibitors in retinoblastoma by augmenting oxidative stress‐mediated apoptosis
Identification of new genetic pathways or molecular targets that sensitize cancer cells to chemotherapeutic drugs may improve the efficacy of current chemotherapy. Here, we report that downmodulation of UHRF1 (ubiquitin‐like with PHD and RING finger domains 1) in retinoblastoma (RB) cells increases...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-02-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12607 |
| _version_ | 1797819826982354944 |
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| author | Jong Kyong Kim Guangyan Kan Yu Mao Zhixuan Wu Xionghong Tan Heng He Chunsik Lee |
| author_facet | Jong Kyong Kim Guangyan Kan Yu Mao Zhixuan Wu Xionghong Tan Heng He Chunsik Lee |
| author_sort | Jong Kyong Kim |
| collection | DOAJ |
| description | Identification of new genetic pathways or molecular targets that sensitize cancer cells to chemotherapeutic drugs may improve the efficacy of current chemotherapy. Here, we report that downmodulation of UHRF1 (ubiquitin‐like with PHD and RING finger domains 1) in retinoblastoma (RB) cells increases the sensitivity to histone deacetylase (HDAC) inhibitors, augmenting apoptotic cell death. We found that UHRF1 depletion downregulates two redox‐responsive genes GSTA4 (glutathione S‐transferase α4) and TXN2 (thioredoxin‐2) in RB cells, and increases the basal level of intracellular oxidative stress. Antioxidant treatment significantly reduced both basal and HDAC inhibitor‐induced DNA damage and apoptosis in UHRF1‐depleted cells. Knockdown of GSTA4 or TXN2 sensitized RB cells to HDAC inhibitors, demonstrating that GSTA4 and TXN2 play key roles in redox homeostasis in RB cells and the susceptibility to HDAC inhibitor treatment upon UHRF1 depletion. In human primary RB, GSTA4 and TXN2 proteins were found to be mostly elevated along with high UHRF1 expression. In addition to augmentation of apoptosis in UHRF1‐depleted RB cells, we also show that UHRF1 downmodulation derepresses the expression of photoreceptor‐specific genes in RB cells in cooperation with a HDAC inhibitor MS‐275 and promotes neuron‐like differentiation. However, further investigation revealed that the enhanced growth‐inhibitory effects of MS‐275 in UHRF1‐depleted cells were still mainly due to robust apoptosis induction rather than differentiation‐mediated growth arrest. Consistent with our findings, UHRF1 depletion in RB cells increased the therapeutic efficacy of MS‐275 in murine orthotopic xenografts. These results provide a novel basis for potential benefits of UHRF1 targeting for RB treatment. |
| first_indexed | 2024-03-13T09:28:22Z |
| format | Article |
| id | doaj.art-8c0b5e5dbf4446f8b51da51d77bcd496 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-13T09:28:22Z |
| publishDate | 2020-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-8c0b5e5dbf4446f8b51da51d77bcd4962023-05-26T04:31:40ZengWileyMolecular Oncology1574-78911878-02612020-02-0114232934610.1002/1878-0261.12607UHRF1 downmodulation enhances antitumor effects of histone deacetylase inhibitors in retinoblastoma by augmenting oxidative stress‐mediated apoptosisJong Kyong Kim0Guangyan Kan1Yu Mao2Zhixuan Wu3Xionghong Tan4Heng He5Chunsik Lee6State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou ChinaState Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou ChinaState Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou ChinaState Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou ChinaState Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou ChinaState Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou ChinaState Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou ChinaIdentification of new genetic pathways or molecular targets that sensitize cancer cells to chemotherapeutic drugs may improve the efficacy of current chemotherapy. Here, we report that downmodulation of UHRF1 (ubiquitin‐like with PHD and RING finger domains 1) in retinoblastoma (RB) cells increases the sensitivity to histone deacetylase (HDAC) inhibitors, augmenting apoptotic cell death. We found that UHRF1 depletion downregulates two redox‐responsive genes GSTA4 (glutathione S‐transferase α4) and TXN2 (thioredoxin‐2) in RB cells, and increases the basal level of intracellular oxidative stress. Antioxidant treatment significantly reduced both basal and HDAC inhibitor‐induced DNA damage and apoptosis in UHRF1‐depleted cells. Knockdown of GSTA4 or TXN2 sensitized RB cells to HDAC inhibitors, demonstrating that GSTA4 and TXN2 play key roles in redox homeostasis in RB cells and the susceptibility to HDAC inhibitor treatment upon UHRF1 depletion. In human primary RB, GSTA4 and TXN2 proteins were found to be mostly elevated along with high UHRF1 expression. In addition to augmentation of apoptosis in UHRF1‐depleted RB cells, we also show that UHRF1 downmodulation derepresses the expression of photoreceptor‐specific genes in RB cells in cooperation with a HDAC inhibitor MS‐275 and promotes neuron‐like differentiation. However, further investigation revealed that the enhanced growth‐inhibitory effects of MS‐275 in UHRF1‐depleted cells were still mainly due to robust apoptosis induction rather than differentiation‐mediated growth arrest. Consistent with our findings, UHRF1 depletion in RB cells increased the therapeutic efficacy of MS‐275 in murine orthotopic xenografts. These results provide a novel basis for potential benefits of UHRF1 targeting for RB treatment.https://doi.org/10.1002/1878-0261.12607chemotherapydrug sensitivityHDAC inhibitorsretinoblastomaUHRF1 |
| spellingShingle | Jong Kyong Kim Guangyan Kan Yu Mao Zhixuan Wu Xionghong Tan Heng He Chunsik Lee UHRF1 downmodulation enhances antitumor effects of histone deacetylase inhibitors in retinoblastoma by augmenting oxidative stress‐mediated apoptosis Molecular Oncology chemotherapy drug sensitivity HDAC inhibitors retinoblastoma UHRF1 |
| title | UHRF1 downmodulation enhances antitumor effects of histone deacetylase inhibitors in retinoblastoma by augmenting oxidative stress‐mediated apoptosis |
| title_full | UHRF1 downmodulation enhances antitumor effects of histone deacetylase inhibitors in retinoblastoma by augmenting oxidative stress‐mediated apoptosis |
| title_fullStr | UHRF1 downmodulation enhances antitumor effects of histone deacetylase inhibitors in retinoblastoma by augmenting oxidative stress‐mediated apoptosis |
| title_full_unstemmed | UHRF1 downmodulation enhances antitumor effects of histone deacetylase inhibitors in retinoblastoma by augmenting oxidative stress‐mediated apoptosis |
| title_short | UHRF1 downmodulation enhances antitumor effects of histone deacetylase inhibitors in retinoblastoma by augmenting oxidative stress‐mediated apoptosis |
| title_sort | uhrf1 downmodulation enhances antitumor effects of histone deacetylase inhibitors in retinoblastoma by augmenting oxidative stress mediated apoptosis |
| topic | chemotherapy drug sensitivity HDAC inhibitors retinoblastoma UHRF1 |
| url | https://doi.org/10.1002/1878-0261.12607 |
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