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Regulation and pharmacological targeting of RAD51 in cancer.

ABSTRACT: Regulation of homologous recombination (HR) is central for cancer prevention. However, too little HR can increase cancer incidence, whereas too much HR can drive cancer resistance to therapy. Importantly, therapeutics targeting HR deficiency have demonstrated a profound efficacy in the clinic improving patient outcomes, particularly for breast and ovarian cancer. RAD51 is central to DNA damage repair in the HR pathway. As such, understanding the function and regulation of RAD51 is essential for cancer biology. This review will focus on the role of RAD51 in cancer and beyond and how modulation of its function can be exploited as a cancer therapeutic.

SUBMITTER: Grundy MK

PROVIDER: S-EPMC7520849 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Regulation and pharmacological targeting of RAD51 in cancer.

Grundy McKenzie K MK Buckanovich Ronald J RJ Bernstein Kara A KA

NAR cancer 20200925 3

Regulation of homologous recombination (HR) is central for cancer prevention. However, too little HR can increase cancer incidence, whereas too much HR can drive cancer resistance to therapy. Importantly, therapeutics targeting HR deficiency have demonstrated a profound efficacy in the clinic improving patient outcomes, particularly for breast and ovarian cancer. RAD51 is central to DNA damage repair in the HR pathway. As such, understanding the function and regulation of RAD51 is essential for ...[more]

PMID: 33015624

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Project description:Rationale: Ovarian cancer is a highly lethal gynecological malignancy with common platinum resistance. Lactylation is involved in multiple biological processes. Thus, we explored the role of histone and non-histone lactylation in platinum resistance, providing a potential therapeutic target to overcome platinum resistance in ovarian cancer. Methods: We utilized gene set enrichment analysis to investigate lactylation-related pathway alterations between platinum-resistant and platinum-sensitive patients from the TCGA cohort. Differential expression of H3K9la was demonstrated using Western blotting and immunohistochemistry. Progression-free and overall survival were determined using a log-rank test. Drug response to cisplatin was evaluated by CCK8, apoptosis flow cytometry, and clonogenic assays in vitro. ChIP-seq and ChIP-qPCR assays were performed to identify downstream targets of H3K9la, which was further confirmed by qRT-PCR. LC-MS/MS was conducted to identify specific lactylation sites for RAD51. Co-IP was used to reveal the interaction between GCN5 and H3K9la or RAD51la. Cell line-derived and patient-derived xenograft (PDX) models of ovarian cancer were constructed for the in vivo experiments. Results: Our study showed elevated histone lactylation, especially of H3K9la, in platinum-resistant ovarian cancer. Moreover, high H3K9la indicated platinum resistance and poor prognosis of ovarian cancer. Impairing H3K9la enhanced response to cisplatin. Mechanistically, H3K9la directly activated RAD51 and BRCA2 expression to facilitate homologous recombination (HR) repair. Furthermore, RAD51K73la enhanced HR repair and subsequently conferred cisplatin resistance. H3K9la and RAD51K73la shared the same upstream regulator, GCN5. Notably, a GCN5 inhibitor remarkably improved the tumor-killing ability of cisplatin in PDX models of ovarian cancer. Conclusions: Our study demonstrated the essential role of histone and RAD51 lactylation in HR repair and platinum resistance. It also identified a potential therapeutic strategy to overcome platinum resistance and improve prognosis in ovarian cancer.

Project description:In conjunction with the endothelin (ET) type A (ETAR) and type B (ETBR) receptors, angiotensin (AT) type 1 (AT1R) and type 2 (AT2R) receptors, are peptide-binding class A G-protein-coupled receptors (GPCRs) acting in a physiologically overlapping context. Angiotensin receptors (ATRs) are involved in regulating cell proliferation, as well as cardiovascular, renal, neurological, and endothelial functions. They are important therapeutic targets for several diseases or pathological conditions, such as hypertrophy, vascular inflammation, atherosclerosis, angiogenesis, and cancer. Endothelin receptors (ETRs) are expressed primarily in blood vessels, but also in the central nervous system or epithelial cells. They regulate blood pressure and cardiovascular homeostasis. Pathogenic conditions associated with ETR dysfunctions include cancer and pulmonary hypertension. While both receptor groups are activated by their respective peptide agonists, pathogenic autoantibodies (auto-Abs) can also activate the AT1R and ETAR accompanied by respective clinical conditions. To date, the exact mechanisms and differences in binding and receptor-activation mediated by auto-Abs as opposed to endogenous ligands are not well understood. Further, several questions regarding signaling regulation in these receptors remain open. In the last decade, several receptor structures in the apo- and ligand-bound states were determined with protein X-ray crystallography using conventional synchrotrons or X-ray Free-Electron Lasers (XFEL). These inactive and active complexes provide detailed information on ligand binding, signal induction or inhibition, as well as signal transduction, which is fundamental for understanding properties of different activity states. They are also supportive in the development of pharmacological strategies against dysfunctions at the receptors or in the associated signaling axis. Here, we summarize current structural information for the AT1R, AT2R, and ETBR to provide an improved molecular understanding.

Dataset Information

Regulation and pharmacological targeting of RAD51 in cancer.

Publications

Regulation and pharmacological targeting of RAD51 in cancer.

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