Targeting the High-Mobility Group Box 3 Protein Sensitizes Chemoresistant Ovarian Cancer Cells to Cisplatin

Abstract

Chemotherapeutic regimens for ovarian cancer often include the use of DNA interstrand crosslink-inducing agents (e.g., platinum drugs) or DNA double-strand break-inducing agents. Unfortunately, the majority of patients fail to maintain a durable response to treatment, in part, due to drug resistance, contributing to a poor survival rate. In this study, we report that cisplatin sensitivity can be restored in cisplatin-resistant ovarian cancer cells by targeting the chromatin-associated high-mobility group box 3 (HMGB3) protein. HMGB proteins have been implicated in the pathogenesis and prognosis of ovarian cancer, and HMGB3 is often upregulated in cancer cells, making it a potential selective target for therapeutic intervention. Depletion of HMGB3 in cisplatin-sensitive and cisplatin-resistant cells resulted in transcriptional downregu-lation of the kinases ATR and CHK1, which attenuated the ATR/CHK1/p-CHK1 DNA damage signaling pathway. HMGB3 was associated with the promoter regions of ATR and CHK1, suggesting a new role for HMGB3 in transcriptional regulation. Furthermore, HMGB3 depletion significantly increased apoptosis in cisplatin-resistant A2780/CP70 cells after cisplatin treatment. Taken together, our results indicate that targeted depletion of HMGB3 attenuates cisplatin resistance in human ovarian cancer cells, increasing tumor cell sensitivity to platinum drugs.Significance: This study shows that targeting HMGB3 is a potential therapeutic strategy to overcome chemoresistance in ovarian cancer.

Nuclear exosome HMGB3 secreted by nasopharyngeal carcinoma cells promotes tumour metastasis by inducing angiogenesis

“…HMGB3 can bind to DNA and bend it 45 . Mukherjee et al 46 reported that HMGB3 promotes DNA damage through the ATR/CHK1/p-CHK1 signalling pathway. Moreover, micronuclei contain not only proteins, but also genomic DNA.…”

Targeting HMGB3/hTERT axis for radioresistance in cervical cancer

“…Also, HMGB1 and HMGB2 facilitate V(D)J recombination by enhance the affinity of the RAG complexes for DNA and increased the cleavage effectiveness [40,41]. Inhibition of HMGB3 in cisplatin-resistant ovarian cancer cells resulted in transcriptional downregulation of ATR and CHK1, subsequently attenuating the ATR/ CHK1/p-CHK1 DNA damage signalling pathway [19]. In our study, we found that down-regulation of HMGB3 significantly impaired the radiation-induced DNA damage repair and increased cell apoptosis.…”

“…HMGB3 has 80% identity with HMGB 1, 2 and may share some functions with them [17]. Previous studies revealed that HMGB3could promote tumor development and maintain dedifferentiation in urinary bladder cancer, oesophageal squamous cancer, gastric cancer, non-small cell lung cancer, breast cancer and hematopathy [18][19][20][21]. Nevertheless, there has not yet been a report about the biological function of HMGB3 in regulating cervical cancer radioresistance.…”

Comprehensive pathway-related genes signature for prognosis and recurrence of ovarian cancer

“…However, the functions of most of the genes in our signatures have not been entirely elucidated. For genes associated with OS, the chromatin-associated high-mobility group box 3 (HMGB3) protein is upregulated and has poor prognosis, and its targeted depletion can attenuate cisplatin resistance in human OC cells ( Mukherjee et al, 2019 ). PYGB has been shown to be upregulated in OC tissue and markedly associated with poor prognosis in OC patients ( Zhou, Jin & Wang, 2019 ).…”