Cotreatment with BCL-2 antagonist sensitizes cutaneous T-cell lymphoma to lethal action of HDAC7-Nur77-based mechanism

Jianguang Chen, Warren Fiskus, Kelly Eaton, Pravina Fernandez, Yongchao Wang, Rekha Rao, Pearl Lee, Rajeshree Joshi, Yonghua Yang, Ravindra Kolhe, Ramesh Balusu, Prasanthi Chappa, Kavita Natarajan, Anand Jillella, Peter Atadja, Kapil N. Bhalla

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Pan-histone deacetylase inhibitors, for example, vorinostat and panobinostat (LBH589; Novartis Pharmaceuticals, East Hanover, NJ), have shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, the molecular basis of this activity remains unclear. HDAC7, a class IIA histone deacetylase (HDAC), is overexpressed in thymocytes, where it represses expression of the proapoptotic nuclear orphan receptor Nur77. Here, we demonstrate that treatment with panobinostat rapidly inhibits the in vitro and intracellular activity, as well as the mRNA and protein levels of HDAC7, and induces expression and translocation of Nur77 to the mitochondria. There, Nur77 converts death resistance protein Bcl-2 into a killer protein, promoting cell death of cultured and patient-derived human CTCL cells. Treatment with panobinostat improved survival of athymic nude mice implanted with human CTCL cells. Ectopic expression of Nur77 induced apoptosis and sensitized HH cells to panobinostat, whereas combined knockdown of Nur77 and its family member Nor1 was necessary to inhibit panobinostat-induced apoptosis of CTCL cells. Cotreatment with the Bcl-2/Bcl-xL antagonist ABT-737 decreased resistance and synergistically induced apoptosis of human CTCL cells. These findings mechanistically implicate HDAC7 and Nur77 in sensitizing human CTCL cells to panobinostat as well as suggest that cotreatment with an anti-Bcl-2 agent would augment the anti-CTCL activity of panobinostat.

Original languageEnglish (US)
Pages (from-to)4038-4048
Number of pages11
JournalBlood
Volume113
Issue number17
DOIs
StatePublished - Nov 17 2009

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Chen, J., Fiskus, W., Eaton, K., Fernandez, P., Wang, Y., Rao, R., Lee, P., Joshi, R., Yang, Y., Kolhe, R., Balusu, R., Chappa, P., Natarajan, K., Jillella, A., Atadja, P., & Bhalla, K. N. (2009). Cotreatment with BCL-2 antagonist sensitizes cutaneous T-cell lymphoma to lethal action of HDAC7-Nur77-based mechanism. Blood, 113(17), 4038-4048. https://doi.org/10.1182/blood-2008-08-176024