UHRF1 Depletion Sensitizes Retinoblastoma Cells to Chemotherapeutic Drugs Via Downregulation of XRCC4

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2018 Feb 9

PMID 29415984

Citations 16

Authors

Heng He

Chunsik Lee

Jong Kyong Kim

Affiliations

Soon will be listed here.

Abstract

UHRF1 (ubiquitin-like with PHD and ring finger domains 1) is highly expressed in various human cancers including retinoblastoma, and associated with tumor-promoting effects such as inhibition of apoptosis and high proliferation. However, the molecular mechanisms underlying tumor-promoting functions of UHRF1 in retinoblastoma still remain elusive. Here, we show that stable knockdown of UHRF1 renders retinoblastoma cells sensitized to conventional chemotherapeutic drugs such as etoposide and camptothecin, resulting in enhanced DNA damage and apoptotic cell death. We found that UHRF1-depleted retinoblastoma cells can recognize DNA damages normally but have markedly low expression of XRCC4 (X-ray repair cross complementing 4) among the components of nonhomologous end-joining (NHEJ) repair complex. Conversely, overexpression of UHRF1 increased the XRCC4 expression and stable knockdown of XRCC4 sensitized retinoblastoma cells to etoposide treatment, suggesting that XRCC4 is a key mediator for the drug sensitivity upon UHRF1 depletion in retinoblastoma cells. Consistent with the findings, chromatin association of DNA ligase IV in response to acute DNA damage was found to be significantly reduced in UHRF1-depleted retinoblastoma cells and functional complementation for XRCC4 in UHRF1-depleted cells attenuated the drug sensitivity, demonstrating that XRCC4 downregulation in UHRF1-depleted cells impaired DNA repair and consequently induced robust apoptosis upon genotoxic drug treatment. In human primary retinoblastoma, high expression of UHRF1 and XRCC4 could be detected, and elevated XRCC4 expression correlated with reduced apoptosis markers, implying that UHRF1-mediated XRCC4 upregulation under pathophysiological conditions triggered by RB1 gene inactivation may confer protection against endogenous DNA damages that arise during retinoblastoma development. Taken together, these results present a new mechanistic insight into how UHRF1 mediates its tumor-promoting functions in retinoblastoma, and also provide a basis for UHRF1 targeting to improve the efficacy of current chemotherapy for retinoblastoma treatment.

Citing Articles

Oncogenic Roles of UHRF1 in Cancer.

Kim A, Benavente C Epigenomes. 2024; 8(3).

PMID: 39051184 PMC: 11270427. DOI: 10.3390/epigenomes8030026.

X-ray cross-complementing family: the bridge linking DNA damage repair and cancer.

Liu Q, Peng Q, Zhang B, Tan Y J Transl Med. 2023; 21(1):602.

PMID: 37679817 PMC: 10483876. DOI: 10.1186/s12967-023-04447-2.

Emerging New Therapeutics for Retinoblastoma.

Raval V, Parulekar M, Singh A Ocul Oncol Pathol. 2023; 8(3):149-155.

PMID: 36938374 PMC: 10015589. DOI: 10.1159/000524919.

Inhibition of Protein Disulfide Isomerase (PDIA1) Leads to Proteasome-Mediated Degradation of Ubiquitin-like PHD and RING Finger Domain-Containing Protein 1 (UHRF1) and Increased Sensitivity of Glioblastoma Cells to Topoisomerase II Inhibitors.

Mouawad R, Neamati N ACS Pharmacol Transl Sci. 2023; 6(1):100-114.

PMID: 36654750 PMC: 9841782. DOI: 10.1021/acsptsci.2c00186.

Genome maintenance in retinoblastoma: Implications for therapeutic vulnerabilities.

Lee C, Kim J Oncol Lett. 2022; 23(6):192.

PMID: 35527780 PMC: 9073582. DOI: 10.3892/ol.2022.13312.

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