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A Novel Potent Class I Hdac Inhibitor Reverses the Stat4/P66shc Apoptotic Defect in B Cells From Chronic Lymphocytic Leukemia Patients Publisher Pubmed



Rossi S1 ; Tatangelo V2 ; Dichiara M1 ; Butini S1 ; Gemma S1 ; Brogi S3 ; Pasquini S4 ; Cappello M5 ; Vincenzi F5 ; Varani K5 ; Lopresti L2 ; Malchiodi M6 ; Carrara C6 ; Gozzetti A6 Show All Authors
Authors
  1. Rossi S1
  2. Tatangelo V2
  3. Dichiara M1
  4. Butini S1
  5. Gemma S1
  6. Brogi S3
  7. Pasquini S4
  8. Cappello M5
  9. Vincenzi F5
  10. Varani K5
  11. Lopresti L2
  12. Malchiodi M6
  13. Carrara C6
  14. Gozzetti A6
  15. Bocchia M6
  16. Marotta G7
  17. Patrussi L2
  18. Carullo G1
  19. Baldari CT2
  20. Campiani G1, 8
Show Affiliations
Authors Affiliations
  1. 1. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, Siena, 53100, Italy
  2. 2. Department of Life Sciences, University of Siena, Via Aldo Moro 2, Siena, 53100, Italy
  3. 3. Department of Pharmacy, University of Pisa, Via Bonanno, Pisa, 56126, Italy
  4. 4. Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Borsari 46, Ferrara, 44121, Italy
  5. 5. Department of Translational Medicine, University of Ferrara, Via Borsari 46, Ferrara, 44121, Italy
  6. 6. Haematology Unit, Department of Medical Sciences, Surgery and Neuroscience, University of Siena, Policlinico “Santa Maria alle Scotte”, Viale Bracci, Siena, 53100, Italy
  7. 7. Stem Cell Transplant and Cellular Therapy Unit, University Hospital, Policlinico “Santa Maria alle Scotte”, Viale Bracci, Siena, 53100, Italy
  8. 8. Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-7346, Iran

Source: Biomedicine and Pharmacotherapy Published:2024


Abstract

Chronic Lymphocytic Leukemia (CLL) patients have a defective expression of the proapoptotic protein p66Shc and of its transcriptional factor STAT4, which evoke molecular abnormalities, impairing apoptosis and worsening disease prognosis and severity. p66Shc expression is epigenetically controlled and transcriptionally modulated by STAT4; epigenetic modifiers are deregulated in CLL cells and specific histone deacetylases (HDACs) like HDAC1, are overexpressed. Reactivation of STAT4/p66Shc expression may represent an attractive and challenging strategy to reverse CLL apoptosis defects. New selective class I HDAC inhibitors (HDACis, 6a-g) were developed with increased potency over existing agents and preferentially interfering with the CLL-relevant isoform HDAC1, to unveil the role of class I HDACs in the upregulation of STAT4 expression, which upregulates p66Shc expression and hence normalizes CLL cell apoptosis. 6c (chlopynostat) was identified as a potent HDAC1i with a superior profile over entinostat. 6c induces marked apoptosis of CLL cells compared with SAHA, which was associated with an upregulation of STAT4/p66Shc protein expression. The role of HDAC1, but not HDAC3, in the epigenetic upregulation of STAT4/p66Shc was demonstrated for the first time in CLL cells and was validated in siRNA-induced HDAC1/HDAC3 knock-down EBV-B cells. To sum up, HDAC1 inhibition is necessary to reactivate STAT4/p66Shc expression in patients with CLL. 6c is one of the most potent HDAC1is known to date and represents a novel pharmacological tool for reversing the impairment of the STAT4/p66Shc apoptotic machinery. © 2024 The Authors
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