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.

<div>Abstract<p>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 downregulation 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 <i>ATR</i> and <i>CHK1</i>, 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.</p>Significance:<p>This study shows that targeting HMGB3 is a potential therapeutic strategy to overcome chemoresistance in ovarian cancer.</p></div>

<p>The Supplementary Materials include figures, which show siRNA-mediated depletion of HMGB1, HMGB2 and HMGB3 proteins in U2OS cells (Supplementary Figure 1), expression levels of HMGB3 in human ovarian cancer cells (Supplementary Figure 2), LD50 values determined from cisplatin treatment of the A2780 and the A2780/CP70 cells via MTT assays (Supplementary Figure 3), and a luciferase assay to demonstrate transcriptional repression by HMGB3 (Supplementary Figure 4). In addition, there are 3 tables showing the siRNA sequences and the primer sequences used to measure gene expression levels and used for ChIP assays.</p>

<p>The Supplementary Materials include figures, which show siRNA-mediated depletion of HMGB1, HMGB2 and HMGB3 proteins in U2OS cells (Supplementary Figure 1), expression levels of HMGB3 in human ovarian cancer cells (Supplementary Figure 2), LD50 values determined from cisplatin treatment of the A2780 and the A2780/CP70 cells via MTT assays (Supplementary Figure 3), and a luciferase assay to demonstrate transcriptional repression by HMGB3 (Supplementary Figure 4). In addition, there are 3 tables showing the siRNA sequences and the primer sequences used to measure gene expression levels and used for ChIP assays.</p>

<div>Abstract<p>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 downregulation 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 <i>ATR</i> and <i>CHK1</i>, 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.</p>Significance:<p>This study shows that targeting HMGB3 is a potential therapeutic strategy to overcome chemoresistance in ovarian cancer.</p></div>