title: BCL11B-Mediated Epigenetic Repression Is a Crucial Target for Histone Deacetylase Inhibitors in Cutaneous T-Cell Lymphoma.
abstract: The treatment options for advanced cutaneous T-cell lymphoma (CTCL) are limited because of its unclear pathogenesis. Histone deacetylase (HDAC) inhibitors (HDACis) are recently developed therapeutics approved for refractory CTCL. However, the response rate is relatively low and unpredictable. Previously, we discovered that BCL11B, a key T-cell development regulator, was aberrantly overexpressed in mycosis fungoides, the most common CTCL, as compared with benign inflammatory skin. In this study, we identified a positive correlation between BCL11B expression and sensitivity to HDACi in CTCL lines. BCL11B suppression in BCL11B-high cells induced cell apoptosis by de-repressing apoptotic pathways and showed synergistic effects with suberoylanilide hydroxamic acid (SAHA), a pan-HDACi. Next, we identified the physical interaction and shared downstream genes between BCL11B and HDAC1/2 in CTCL lines. This interaction was essential in the anti-apoptosis effect of BCL11B, and the synergism between BCL11B suppression and HDACi treatment. Further, in clinical samples from 46 mycosis fungoides patients, BCL11B showed increased but varied expression in advanced tumor stage. Analysis of four patients receiving SAHA treatment suggested a positive correlation between BCL11B expression and favorable response to SAHA treatment. In conclusion, BCL11B may serve as a therapeutic target and a useful marker for improving HDACi efficacy in advanced CTCL.
authors.affiliation: Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China; Department of Dermatology and Venerology, Binzhou Medical University Hospital, Binzhou, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Fu
authors.affiliation: Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China.
authors.forename: Shengguo
authors.initials: S
authors.lastname: Yi
authors.affiliation: Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China.
authors.forename: Jingru
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Tu
authors.affiliation: Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China. Electronic address: yangwang_dr@bjmu.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D017209:Apoptosis; D063185:Epigenetic Repression; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics*; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D016335:Zinc Fingers
chemical_list: C479740:BCL11B protein, human; D056572:Histone Deacetylase Inhibitors; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins