HuR Reduces Radiation-Induced DNA Damage by Enhancing Expression of ARID1A

Abstract

Tumor suppressor ARID1A, a subunit of the chromatin remodeling complex SWI/SNF, regulates cell cycle progression, interacts with the tumor suppressor TP53, and prevents genomic instability. In addition, ARID1A has been shown to foster resistance to cancer therapy. By promoting non-homologous end joining (NHEJ), ARID1A enhances DNA repair. Consequently, ARID1A has been proposed as a promising therapeutic target to sensitize cancer cells to chemotherapy and radiation. Here, we report that ARID1A is regulated by human antigen R (HuR), an RNA-binding protein that is highly expressed in a wide range of cancers and enables resistance to chemotherapy and radiation. Our results indicate that HuR binds ARID1A mRNA, thereby increasing its stability in breast cancer cells. We further find that ARID1A expression suppresses the accumulation of DNA double-strand breaks (DSBs) caused by radiation and can rescue the loss of radioresistance triggered by HuR inhibition, suggesting that ARID1A plays an important role in HuR-driven resistance to radiation. Taken together, our work shows that HuR and ARID1A form an important regulatory axis in radiation resistance that can be targeted to improve radiotherapy in breast cancer patients.

Molecular Targeting of HuR Oncoprotein Suppresses MITF and Induces Apoptosis in Melanoma Cells

“…However, HuR-NP did not alter the cell cycle phases in melanocytes at 24 h and 48 h after treatment. Our results revealed that the HuR-NP treatment selectively induced a G1 phase cell-cycle arrest in melanoma cells but not in melanocytes and concurred with previous results reported for other solid tumors [ 30 , 31 , 44 ].…”

“…Cisplatin (CDDP; 10 µg)-treated cells were used as a positive control in the annexin V assay. The ability of HuR-NP treatment inducing apoptosis in melanoma cells but not in melanocytes is in agreement with prior reports showing HuR inhibition in tumor cells but not in normal cells results in apoptotic cell death [30,31,44].…”

“…Cisplatin (CDDP; 10 µg)-treated cells were used as a positive control in the annexin V assay. The ability of HuR-NP treatment inducing apoptosis in melanoma cells but not in melanocytes is in agreement with prior reports showing HuR inhibition in tumor cells but not in normal cells results in apoptotic cell death [30,31,44]. Correlating with caspase activation in the melanoma cells was a significant increase in annexin-V-positive staining in HuR-NP-treated MeWo cells at 24 h (16% increase over controls) and 48 h (12% increase over controls), respectively, compared to C-NP-treated and untreated cells (Figure 4B; p < 0.05).…”

RNA-Targeted Therapies and High-Throughput Screening Methods

“…However, the evidence is not sufficient to prove the SAR of coumarin derivatives as HuR/ARE disruptors and the binding interface has not been confirmed. In particular, CMLD-2 showed therapeutic potentials in lung, breast, and thyroid cancer cells in vitro, with implicated mechanisms relevant to HuR-RNA disruption [143][144][145].…”

MicroRNA‐324‐5p affects the radiotherapy response of cervical cancer via targeting ELAV‐like RNA binding protein 1

“…6 The biological function of ELAVL1 is implicated in gametogenesis, placental growth, 7,8 and cell survival. 9 In addition, ELAVL1 can mediate the progression of inflammation and angiogenesis. 10 Moreover, previous studies have indicated that ELAVL1 can participate in the occurrence of malignant tumours.…”