SATB1 overexpression promotes malignant T-cell proliferation in cutaneous CD30+lymphoproliferative disease by repressing p21

Cutaneous CD30+lymphoproliferative disease (CD30+LPD), characterized by the presence of CD30+anaplastic large T cells, comprises the second most common group of cutaneous T-cell lymphoma (CTCL). However, little is known about the pathobiology of the CD30+lymphoma cells, as well as the mechanisms of disease progression. Here we report that Special AT-rich region binding protein 1 (SATB1), a thymocyte specific chromatin organizer, is over-expressed in CD30+lymphoma cells in most CD30+LPDs, and its expression is upregulated during disease progression. Our findings show that SATB1 silencing in CD30+LPD cells leads to G1 cell cycle arrest mediated by p21 activation. Using chromatin immunoprecipitation, luciferase assays, and mutational analysis, we demonstrate that SATB1 directly regulates the transcription of p21 in a p53-independent manner. Moreover, DNA demethylation on a specific CpG-rich region of the SATB1 promoter is associated with the upregulation of SATB1 during disease progression. These experiments define a novel SATB1-p21 pathway in malignant CD30+T lymphocytes, which provides novel molecular insights into the pathogenesis of CD30+LPDs and possibly leads to new therapies.