Angiogenesis, the formation of new blood vessels from preexisting ones, is essential for normal development, wound healing, and tissue repair. However, dysregulated angiogenesis is implicated in various pathological conditions, including cancer, diabetic retinopathy, and atherosclerosis. Epigenetic modifications, including DNA methylation, histone modification, and noncoding RNAs (e.g., miRNAs), play a crucial role in regulating angiogenic gene expression without altering the underlying DNA sequence. These modifications tightly regulate the balance between pro-angiogenic and anti-angiogenic factors, thereby influencing endothelial cell proliferation, migration, and tube formation. In recent years, epigenetic drugs, such as DNA methyltransferase inhibitors (e.g., azacitidine, decitabine), histone deacetylase inhibitors (e.g., vorinostat, romidepsin), and BET inhibitors (e.g., JQ1), have emerged as promising therapeutic strategies for targeting abnormal angiogenesis. These agents modulate gene expression patterns, reactivating silenced tumor suppressor genes while downregulating pro-angiogenic signaling pathways. Additionally, miRNA modulators, such as MRG-110 and MRG-201, provide precise regulation of angiogenesis-related pathways, demonstrating significant therapeutic potential in preclinical models. This review underscores the intricate interplay between epigenetic regulation and angiogenesis, highlighting key mechanisms and therapeutic applications. Advancing our understanding of these processes will enable the development of more effective and targeted epigenetic therapies for angiogenesis-related diseases, paving the way for innovative clinical interventions.

Abstract Drug resistance in epithelial ovarian cancer is reportedly attributed to the existence of cancer stem cells, because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers by targeting cancer stem cells. We screened an FDA-approved compound and clinical libraries, and found several small molecule drugs that target ovarian CSCs. These drugs decreased sphere formation, viability, and proliferation, and induced apoptosis in ovarian CSCs. Since these drugs harbor target proteins, we investigated the expression of the target proteins in ovarian CSC and found the increased level of the protein expression and new therapeutic markers of ovarian CSCs. Downregulation of these genes reduced the stem-cell-like properties of ovarianCSCs. Expressions of these three genes are negatively correlated with the survival rate of patient groups. In combination therapy with chemo agents, synergistic ect was shown in inhibiting the viability and proliferation of ovarian CSCs. Our results suggested that these may be potential therapeutic drugs for preventing ovarian cancer recurrence. Citation Format: Dong Kyu Choi, Sang Hyun Min. Screening of novel therapeutic markers for ovarian cancer stem cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A021.

Angiogenesis, the formation of new blood vessels from preexisting ones, is essential for normal development, wound healing, and tissue repair. However, dysregulated angiogenesis is implicated in various pathological conditions, including cancer, diabetic retinopathy, and atherosclerosis. Epigenetic modifications, including DNA methylation, histone modification, and noncoding RNAs (e.g., miRNAs), play a crucial role in regulating angiogenic gene expression without altering the underlying DNA sequence. These modifications tightly regulate the balance between pro-angiogenic and anti-angiogenic factors, thereby influencing endothelial cell proliferation, migration, and tube formation. In recent years, epigenetic drugs, such as DNA methyltransferase inhibitors (e.g., azacitidine, decitabine), histone deacetylase inhibitors (e.g., vorinostat, romidepsin), and BET inhibitors (e.g., JQ1), have emerged as promising therapeutic strategies for targeting abnormal angiogenesis. These agents modulate gene expression patterns, reactivating silenced tumor suppressor genes while downregulating pro-angiogenic signaling pathways. Additionally, miRNA modulators, such as MRG-110 and MRG-201, provide precise regulation of angiogenesis-related pathways, demonstrating significant therapeutic potential in preclinical models. This review underscores the intricate interplay between epigenetic regulation and angiogenesis, highlighting key mechanisms and therapeutic applications. Advancing our understanding of these processes will enable the development of more effective and targeted epigenetic therapies for angiogenesis-related diseases, paving the way for innovative clinical interventions.

Abstract Drug resistance in epithelial ovarian cancer is reportedly attributed to the existence of cancer stem cells, because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers by targeting cancer stem cells. We screened an FDA-approved compound and clinical libraries, and found several small molecule drugs that target ovarian CSCs. These drugs decreased sphere formation, viability, and proliferation, and induced apoptosis in ovarian CSCs. Since these drugs harbor target proteins, we investigated the expression of the target proteins in ovarian CSC and found the increased level of the protein expression and new therapeutic markers of ovarian CSCs. Downregulation of these genes reduced the stem-cell-like properties of ovarianCSCs. Expressions of these three genes are negatively correlated with the survival rate of patient groups. In combination therapy with chemo agents, synergistic ect was shown in inhibiting the viability and proliferation of ovarian CSCs. Our results suggested that these may be potential therapeutic drugs for preventing ovarian cancer recurrence. Citation Format: Dong Kyu Choi, Sang Hyun Min. Screening of novel therapeutic markers for ovarian cancer stem cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A021.

Histone modifications, including histone lysine methylation, regulate gene expression in the vasculature, and targeting tumor blood vessels through histone modification decreases tumor growth. SETD8, a methyltransferase that catalyzes the mono-methylation of histone H4 lysine 20 is known to promote tumorigenesis in various cancers and its high levels of expression are related to poor prognosis. However, the detailed mechanisms by which SETD8 stimulates tumor progression and angiogenesis are still not well understood. Recent studies have demonstrated that, in vitro, BVT-948 efficiently and selectively suppresses SETD8 activity and histone methylation levels. In this study, we showed that BVT-948-mediated SETD8 inhibition in HUVECs results in an inhibition of angiogenesis. Inhibition of SETD8 not only inhibited angiogenesis but also disrupted actin stress fiber formation and induced cell cycle arrest at S phase. These effects were accompanied by increased HES-1 expression levels, decreased osteopontin levels, and a decreased differentiation of human induced pluripotent stem cells into endothelial cells. Interestingly, BVT-948 treatment reduced pathological angiogenesis in mouse OIR model. These data illustrate the mechanisms by which SETD8 regulates angiogenesis and may enable the use of a SETD8 inhibitor to treat various pathological conditions that are known to be associated with excessive angiogenesis, including and tumor growth.

Osteoporosis is a major skeletal disorder characterized by reduced bone strength and increased risk of fractures. Excessive osteoclast-mediated bone resorption is a primary cause of this condition, underscoring the need for effective anti-resorptive therapies. N-phenyl-methylsulfonamido-acetamide (PMSA) compounds have been previously identified as potential anti-resorptive agents that inhibit osteoclastogenesis. In this study, ribonucleic acid (RNA)-sequencing and proteomic analyses identified calcineurin (CaN) as a potential target of PMSA implicated in osteoclast differentiation. PMSA bound to CaN and suppressed its phosphatase activity, which is essential for the activation and translocation of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a key regulator of osteoclastogenesis. PMSA treatment resulted in altered NFATc1-related signaling and increased phospho-NFATc1 levels in osteoclasts. Overall, these findings suggest that PMSA may inhibit CaN activity during osteoclast differentiation, positioning it as a promising therapeutic candidate for osteoporosis.

mice further exacerbated the loss of dopaminergic neurons, aggravated motor impairments, and enhanced activation of apoptosis effector caspase-3. These results suggest that down-regulation of HSPA9 may contribute to the development and progression of PD, potentially offering a new therapeutic strategy for PD treatment.

Apples and Korean green chili peppers are rich in phytochemicals and recognized for their diverse bioactive properties. Given the potential to enhance these beneficial compounds, this study investigated the effects of mineral supplementation during cultivation on the antioxidant and antiproliferative activities of extracts from both crops. Mineral-enriched cultivation significantly increased the total phenolic and flavonoid contents in both crops, which was accompanied by enhanced DPPH and ABTS radical scavenging activities. Moreover, the mineral-supplemented extracts of Korean green chili pepper activated the Nrf2 signaling pathway and upregulated downstream antioxidant enzymes, including heme oxygenase-1 (HO-1), γ-glutamylcysteine ligase (GCL), and glutathione peroxidase (GPx). Notably, the mineral-supplemented Korean green chili pepper extract significantly suppressed the proliferation of human colorectal cancer cells. These findings suggest that mineral supplementation during cultivation may improve the functional quality of apples and Korean green chili peppers, supporting their potential application in cancer prevention and complementary therapeutic strategies.

Primary cilia are dynamic signaling hubs essential for cell homeostasis, and defects in ciliogenesis underpin various genetic disorders. Alpha-hydroxyacyl-CoA dehydrogenase (HADHA), a subunit of the mitochondrial trifunctional enzyme, is crucial for long-chain fatty acid β-oxidation and acetyl-CoA production. Although it was recently demonstrated that lipid metabolism modulates primary ciliogenesis, the connection between mitochondrial β-oxidation and primary cilia remains largely unexplored. Here, we report that HADHA dysfunction markedly impairs primary ciliogenesis and disrupts cilia-dependent signaling. Loss of HADHA reduces both ciliary frequency and length, accompanied by decreased levels of key ciliary signaling mediators. Reintroduction of wild-type HADHA in HADHA knockout cells rescues these defects, whereas its dehydrogenase deficiency mutant (E510Q) fails to restore either normal cilia formation or ciliary signaling. Notably, supplementation with sodium acetate, which resupplies intracellular acetyl-CoA, effectively rescues primary cilium in HADHA-deficient cells. Importantly, this acetate-mediated rescue implicates a potential therapeutic strategy for HADHA-related disorders, supporting the translational relevance of modulating acetyl-CoA levels to restore ciliary function. These findings suggest a relevant link between mitochondrial β-oxidation and primary ciliogenesis, highlighting acetyl-CoA as a potential therapeutic target for disorders related to HADHA deficiency.