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Torres HM, VanCleave AM, Vollmer M, et al. Selective Targeting of Class I Histone Deacetylases in a Model of Human Osteosarcoma. Cancers (Basel). 2021;13(16)doi: 10.3390/cancers13164199.
Torres, H. M., VanCleave, A. M., Vollmer, M., Callahan, D. L., Smithback, A., Conn, J. M., Rodezno-Antunes, T., Gao, Z., Cao, Y., Afeworki, Y., & Tao, J. (2021). Selective Targeting of Class I Histone Deacetylases in a Model of Human Osteosarcoma. Cancers, 13(16), . https://doi.org/10.3390/cancers13164199
Torres, Haydee M, et al. "Selective Targeting of Class I Histone Deacetylases in a Model of Human Osteosarcoma." Cancers vol. 13,16 (2021). doi: https://doi.org/10.3390/cancers13164199
Torres HM, VanCleave AM, Vollmer M, Callahan DL, Smithback A, Conn JM, Rodezno-Antunes T, Gao Z, Cao Y, Afeworki Y, Tao J. Selective Targeting of Class I Histone Deacetylases in a Model of Human Osteosarcoma. Cancers (Basel). 2021 Aug 20;13(16). doi: 10.3390/cancers13164199. PMID: 34439353; PMCID: PMC8394112.
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Cancers (Basel). 2021 Aug 20;13(16). doi: 10.3390/cancers13164199.

Selective Targeting of Class I Histone Deacetylases in a Model of Human Osteosarcoma.

Cancers

Haydee M Torres, Ashley M VanCleave, Mykayla Vollmer, Dakota L Callahan, Austyn Smithback, Josephine M Conn, Tania Rodezno-Antunes, Zili Gao, Yuxia Cao, Yohannes Afeworki, Jianning Tao

Affiliations

  1. Cancer Biology & Immunotherapies Group at Sanford Research, Sioux Falls, SD 57104, USA.
  2. Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD 57007, USA.
  3. Medical Student Research Program, University of South Dakota, Vermillion, SD 57069, USA.
  4. Sanford Program for Undergraduate Research, University of Sioux Falls, Sioux Falls, SD 57104, USA.
  5. Sanford PROMISE Scholar Program, Harrisburg High School, Sioux Falls, SD 57104, USA.
  6. Sanford Program for Undergraduate Research, Carleton College, Northfield, MN 55057, USA.
  7. Flow Cytometry Core at Sanford Research, Sioux Falls, SD 57104, USA.
  8. Functional Genomics & Bioinformatics Core Facility at Sanford Research, Sioux Falls, SD 57104, USA.
  9. Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA.

PMID: 34439353 PMCID: PMC8394112 DOI: 10.3390/cancers13164199

Abstract

Dysregulation of histone deacetylases (HDACs) is associated with the pathogenesis of human osteosarcoma, which may present an epigenetic vulnerability as well as a therapeutic target. Domatinostat (4SC-202) is a next-generation class I HDAC inhibitor that is currently being used in clinical research for certain cancers, but its impact on human osteosarcoma has yet to be explored. In this study, we report that 4SC-202 inhibits osteosarcoma cell growth in vitro and in vivo. By analyzing cell function in vitro, we show that the anti-tumor effect of 4SC-202 involves the combined induction of cell-cycle arrest at the G2/M phase and apoptotic program, as well as a reduction in cell invasion and migration capabilities. We also found that 4SC-202 has little capacity to promote osteogenic differentiation. Remarkably, 4SC-202 revised the global transcriptome and induced distinct signatures of gene expression in vitro. Moreover, 4SC-202 decreased tumor growth of established human tumor xenografts in immunodeficient mice in vivo. We further reveal key targets regulated by 4SC-202 that contribute to tumor cell growth and survival, and canonical signaling pathways associated with progression and metastasis of osteosarcoma. Our study suggests that 4SC-202 may be exploited as a valuable drug to promote more effective treatment of patients with osteosarcoma and provide molecular insights into the mechanism of action of class I HDAC inhibitors.

Keywords: 4SC-202; domatinostat; epigenetics; histone deacetylase inhibitor; osteoblast-like differentiation; osteosarcoma; signaling pathways; transcriptome; xenografts

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