The Overexpression of Enhancer of Zeste Homologue 2 Is Associated with Tumor Proliferation and Aggressive Behavior in Adult T-Cell Leukemia/Lymphoma.

Enhancer of zeste homologue 2 (EZH2) is a critical component of the Polycomb Repressive Complexes PRC2, which mediates epigenetic gene silencing by the trimethylation of Lys27 of histone 3 (H3K27). This regulation is not only involved in embryonic development and stem cell renewal, but also in tumor progression. Adult T-cell leukemia/lymphoma (ATLL) is a single disease entity etiologically associated with human T-cell leukemia virus type-1 (HTLV-1). Its clinical behavior, however, is quite diverse among patients and is thus subclassified into several subtypes. The prognosis of the aggressive subtypes is very poor based on standard chemotherapy, and so the development of a new therapeutic approach is urgent.

In a comparative microarray analysis of primary ATLL samples, the acute type showed significantly higher EZH2, YY1, and RYBP (RING1 and YY1 binding protein) expressions compared with the chronic type. Further analysis employing real-time quantitative RT-PCR of various Polycomb group (PcG)-related proteins, including the ones mentioned above, revealed that the mRNAs of two other PRC2 components, EED and RBBP4, were also significantly elevated in ATLL, irrespective of the subtypes, compared with lymphocytes from HTLV-1 carriers. These results suggest that the dysregulation of PRC2 is a key event in the development and progression of ATLL. In the immunohistochemical analysis of ATLL lymph nodes, the nuclei of over 90% of ATLL cells were positive for EZH2, which in clear contrast to reactive or indolent B-lymphoma lymph nodes in which a few cells were positive. It has been shown that activated Akt phosphorylates EZH2 at serine 21 and suppresses its methyltransferase activity. Western blotting of EZH2 showed that EZH2 of primary ATLL cells was not phospholyrated and remained in its active form. Indeed, the trimethylation of H3K27 in ATLL cells was confirmed by Western blotting and immunohistochemistry, whereas it was completely absent in lymphocytes from HTLV-1 carriers. Finally, in studies using ATLL cell lines, the knockdown of EZH2 by siRNA caused decrease in cell proliferation. Moreover, ATLL cell lines showed high sensitivities to histone deacetylase (HDAC) inhibitors as LBH589, and LBH589 decreased EZH2 expression. EZH2 inhibitor 3-deazaneplancin A (DZNeP) also reduced cell growth, not only in primary ATLL cells, but also in ATLL cells lines. These results strongly support the rationale for developing molecular targeting therapies against EZH2 in ATLL.

No relevant conflicts of interest to declare.