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

Author:

Chen Jianguang1,Fiskus Warren1,Eaton Kelly1,Fernandez Pravina1,Wang Yongchao1,Rao Rekha1,Lee Pearl1,Joshi Rajeshree1,Yang Yonghua1,Kolhe Ravindra1,Balusu Ramesh1,Chappa Prasanthi1,Natarajan Kavita1,Jillella Anand1,Atadja Peter2,Bhalla Kapil N.1

Affiliation:

1. Medical College of Georgia Cancer Center, Augusta; and

2. Novartis Institute for Biomedical Research, Cambridge, MA

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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