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Discovery of a novel HDACi structure that inhibits the proliferation of ovarian cancer cells in vivo and in vitro.

ABSTRACT: Histone deacetylases (HDACs) exhibit increased expression in cancer and promote oncogenesis via the acetylation of or interactions with key transcriptional regulators. HDAC inhibitors (HDACis) decrease HDAC activity to selectively inhibit the occurrence and development of tumors. Our study screened and obtained a new HDACi structure. In vitro experiments have showed that among the leads, Z31216525 significantly inhibited the proliferation and induced the apoptosis of epithelial ovarian cancer (EOC) cells. In vivo experiments demonstrated that compared to the control, Z31216525 significantly inhibited tumor growth and showed very low toxicity. Further mechanistic studies revealed that Z31216525 may exert an antitumor effect by inhibiting the expression of the c-Myc gene. Collectively, our studies identified a novel HDACi that is expected to become a new potential therapeutic drug for EOC and has important value for the design of new HDACi structures.

SUBMITTER: Bai M

PROVIDER: S-EPMC8416734 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Discovery of a novel HDACi structure that inhibits the proliferation of ovarian cancer cells in vivo and in vitro.

Bai Miao M Cui Mengqi M Li Mingyue M Yao Xinlei X Wu Yulun Y Zheng Lihua L Sun Luguo L Song Qiuhang Q Wang Shuyue S Liu Lei L Yu Chunlei C Huang Yanxin Y

International journal of biological sciences 20210812 13

Histone deacetylases (HDACs) exhibit increased expression in cancer and promote oncogenesis via the acetylation of or interactions with key transcriptional regulators. HDAC inhibitors (HDACis) decrease HDAC activity to selectively inhibit the occurrence and development of tumors. Our study screened and obtained a new HDACi structure. In vitro experiments have showed that among the leads, Z31216525 significantly inhibited the proliferation and induced the apoptosis of epithelial ovarian ca ...[more]

PMID: 34512161

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Project description:BackgroundThis study sought to analyze long non-coding ribonucleic acid (lncRNA) LINC00273 expression in ovarian cancer tissues, and to preliminarily explore its effect on the growth and invasion of ovarian cancer cells and its influencing mechanism.MethodsQuantitative real-time polymerase chain reaction was performed to detect the LINC00273 expression levels of cancerous ovarian tissues and their related cell lines. The ovarian cancer cells with the highest expression of LINC00273 were transfected with a knockdown lentiviral vector targeting the LINC00273 sequence and a negative control plasmid. The effects of the LINC00273 knockdown on the invasion and growth of these cancerous cells were evaluated by clonogenic assays, flow cytometry, EdU (5-Ethynyl-2'-deoxyuridine), Cell Counting Kit-8, and Transwell assays. Western Blot was used to measure the LINC00273 knockdown effects on invasion and migration-related gene expression, and the knockdown effects on the ovarian proliferation ability of the cancer cells in vivo were analyzed by in vivo nude mouse experiments.ResultsLINC00273 expression was significantly more increased in the cancerous ovarian tissues than the adjacent tissues. The LINC00273 expression of the ovarian cancer cell lines was higher than that of the normal ovarian epithelial cells. LINC00273 knockdown greatly suppressed the proliferative and clonogenic function of these cancerous cells. The flow cytometry results revealed that LINC00273 knockdown notably induced G0/G1 phase arrest in the ovarian cancer cells. LINC00273 knockdown also promoted E-cadherin expression in the ovarian cancer cells, and inhibited vimentin, matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and N-cadherin, expression to inhibit the invasion and migration ability of the ovarian cancer cells. The in vivo experiments indicated that LINC00273 knockdown suppressed in vivo cancer cell proliferation in the ovaries.ConclusionsLINC00273 is highly expressed in both ovarian cancerous tissues and ovarian cancerous cell lines. LINC00273 knockdown greatly suppressed the proliferative and invasive capabilities of the cancerous ovarian cells. In terms of the molecular process, it may be that the knockdown of LINC00273 promotes E-cadherin and inhibits vimentin, N-cadherin, MMP-2, and MMP-9 expression in cancerous ovarian cells.

Project description:Purpose: Recent studies indicate that pregnancy upregulated non-ubiquitous calmodulin kinase (PNCK) is significantly up-regulated in breast and renal carcinomas. However, the expression profile and its biological relevance of PNCK in nasopharyngeal carcinoma (NPC) have not been elucidated. Methods: The expression level of PNCK was detected in specimens of NPC (n=10) and normal tissues (n=10) by real-time PCR and immunohistochemistry. Celigo Cell Counting and MTT assay were used to measure cell viability. Apoptosis was detected by flow cytometric analysis and caspases 3/7 activity assay. Real-time PCR and Western blotting were performed to evaluate the expression of PNCK. The bioluminescence imaging was used to evaluate the effects of PNCK knockdown on tumor growth using a xenograft animal model. The global gene expression profile was determined in wild type and PNCK-depleted CNE-2 cells via transcriptomics analysis. For mechanical investigation, the changes of PI3K/AKT/mTOR signaling pathway were detected by Western blotting. Results: The mRNA and protein levels of PNCK were increased in human NPC samples. In vitro experiments showed that shRNA or CRISPR-Cas9 mediated silencing of PNCK inhibited proliferation and induced apoptosis in NPC cells. In addition, in vivo assay revealed that knockdown of PNCK suppressed tumor growth. Consistently, a significant reduction of tumor bioluminescence in mice inoculated with PNCK-knockdown cells compared to that of control cells. In gene expression, the transcriptomics analysis revealed that there were 589 upregulated genes and 589 downregulated genes in PNCK-knockdown cells. Ingenuity Pathway Analysis (IPA) identified significant changes of PI3K/AKT/mTOR signaling pathway in PNCK-knockdown cells. Furthermore, western blot analysis revealed that interference with PNCK reduced the phosphorylation levels of PI3K, AKT and mTOR in CNE-2 cells. Conclusion: This study for the first time demonstrates that knockdown of PNCK could suppress growth and induce apoptosis of NPC cells both in vitro and in vivo by regulating PI3K/AKT/mTOR signaling pathway. These findings suggest that PNCK might be a novel therapeutic target for NPC treatment.

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Discovery of a novel HDACi structure that inhibits the proliferation of ovarian cancer cells in vivo and in vitro.

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Discovery of a novel HDACi structure that inhibits the proliferation of ovarian cancer cells <i>in vivo</i> and <i>in vitro</i>.

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