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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. [ABSTRACT FROM AUTHOR]

Retinoblastoma (RB) is a pediatric ocular malignancy that is initiated mostly by biallelic inactivation of the RB transcriptional corepressor 1 (RB1) tumor suppressor gene in the developing retina. Unlike the prevailing prediction based on multiple studies involving RB1 gene disruption in experimental models, human RB tumors have been demonstrated to possess a relatively stable genome, characterized by a low mutation rate and a few recurrent chromosomal alterations related to somatic copy number changes. This suggests that RB may harbor heightened genome maintenance mechanisms to counteract or compensate for the risk of massive genome instability, which can potentially be driven by the early RB1 loss as a tumor-initiating event. Although the genome maintenance mechanisms might have been evolved to promote RB cell survival by preventing lethal genomic defects, emerging evidence suggests that the dependency of RB cells on these mechanisms also exposes their unique vulnerability to chemotherapy, particularly when the genome maintenance machineries are tumor cell-specific. This review summarizes the genome maintenance mechanisms identified in RB, including findings on the roles of chromatin regulators in DNA damage response/repair and protein factors involved in maintaining chromosome stability and promoting survival in RB. In addition, advantages and challenges for exploiting these therapeutic vulnerabilities in RB are discussed. [ABSTRACT FROM AUTHOR]