UHRF1 downmodulation enhances antitumor effects of histone deacetylase inhibitors in retinoblastoma by augmenting oxidative stress‐mediated apoptosis

Autor: Heng He, Yu Mao, Zhixuan Wu, Guangyan Kan, Xionghong Tan, Jong Kyong Kim, Chunsik Lee
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Cancer Research
Apoptosis
medicine.disease_cause
chemotherapy
Histones
Mice
0302 clinical medicine
Thioredoxins
HDAC inhibitors
RNA-Seq
Research Articles
Glutathione Transferase
Gene knockdown
Mice
Inbred BALB C
Retinoblastoma
Chemistry
Acetylation
Cell Differentiation
General Medicine
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Oncology
030220 oncology & carcinogenesis
Gene Knockdown Techniques
Molecular Medicine
Female
Oxidation-Reduction
Photoreceptor Cells
Vertebrate
Research Article
Chromatin Immunoprecipitation
DNA damage
Cell Survival
Retinal Neoplasms
Ubiquitin-Protein Ligases
Mice
Nude
Antineoplastic Agents
lcsh:RC254-282
retinoblastoma
03 medical and health sciences
Cell Line
Tumor
Genetics
medicine
Animals
Humans
drug sensitivity
UHRF1
TXN2
medicine.disease
Xenograft Model Antitumor Assays
Histone Deacetylase Inhibitors
Oxidative Stress
030104 developmental biology
Cancer cell
Cancer research
CCAAT-Enhancer-Binding Proteins
Histone deacetylase
Oxidative stress
Zdroj: Molecular Oncology, Vol 14, Iss 2, Pp 329-346 (2020)
Molecular Oncology
ISSN: 1574-7891
1878-0261
Popis: 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.
This study presents two novel tumor‐promoting functions of UHRF1 in retinoblastoma (RB). UHRF1 regulates reactive oxygen species (ROS)‐detoxifying genes to counteract the accumulation of intracellular ROS and thereby protects the cells from histone deacetylase (HDAC) inhibitor‐induced apoptosis. On the other hand, UHRF1 participates in repression of photoreceptor differentiation as a corepressor in a multiprotein complex containing HDAC to repress photoreceptor‐specific genes in RB cells.
Databáze: OpenAIRE
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