Abstract Histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) are overexpressed in cancer cells associated with dysregulated gene expression and tumor progression. DNMT1 partnered with Class I HDAC as complex to inhibit gene transcription. Several pan-HDAC inhibitors have been approved for T-cell lymphoma with evident side effects. More selective HDAC inhibitors need to be developed. Psammaplin A (PsA), a symmetrical bromotyrosine-derived disulfide dimer isolated from the Psammaplysilla sponge, is a selective Class I HDAC inhibitor. We tested its cell growth inhibition and apoptosis induction in 12 hematological malignant cell lines with 8 lines sensitive (more than 50% growth inhibition at 1 μM) and 4 lines insensitive (less than 20% growth inhibition at 1 μM). PsA induces acetylation of H3, but not α-tubulin, supporting the Class I HDAC inhibition selection. In the sensitive cell lines, PsA induces apoptosis with down-regulation of c-Flip and upregulation of NOXA as well as DNA damage detected by γ-H2A.X. RNA sequence analysis results confirm the regulation of PsA on NOXA, c-Flip and p21 gene expression. The four insensitive cell lines express high levels of DNMT1 with resistance to apoptosis induction. Silencing DNMT1 with siRNA sensitizes PsA-induced apoptosis with induction of NOXA and γ-H2A.X. Azacytidine, the DNMT1 degrader, in combination with PsA induce synergistic cell growth inhibition and apoptosis in vitro. PsA (20 mg/kg) plus Azacytidine (2.5 mg/kg) synergistically inhibit tumor growth in insensitive mantle cell lymphoma Jeko-1 xenografts, without detected toxic signs in organ pathological analysis. We find a new mechanism of DNMT1 controlling the sensitivity of Class I HDAC inhibitor PsA and provide a rationale of PsA with azacytidine for combination therapy. Citation Format: Yu Bao, Dan Liu, Zi Wu, Yumei He, Ping Gong, Samuel Waxman, Yongkui Jing. DNMT1 determines the sensitivity of Class I HDAC inhibitor Psammaplin A to induce apoptosis and DNA damage in hematological malignant cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4579.
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