The Novel Histone Deacetylase Inhibitor, OBP-801, Induces Apoptosis in Rhabdoid Tumors by Releasing the Silencing of <i>NOXA</i>

Abstract

Rhabdoid tumor is an aggressive, early childhood tumor. Biallelic inactivation of the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (<i>SMARCB1</i>)/integrase interactor 1 (<i>INI1</i>) gene is the only common genetic feature in rhabdoid tumors. Loss of <i>SMARCB1</i> function results in downregulation of several tumor suppressor genes including <i>p16, p21</i>, and <i>NOXA</i> The novel histone deacetylase inhibitor, OBP-801, induces <i>p21</i> and has shown efficacy against various cancers. In our study, OBP-801 strongly inhibited the cell growth of all rhabdoid tumor cell lines in WST-8 assay. However, Western blotting and cell-cycle analysis revealed that OBP-801 did not activate the P21-RB pathway in some cell lines. <i>p21</i> knockout indicated that <i>p21</i> did not dominate the OBP-801 antitumor effect in rhabdoid tumor cell lines. We discovered that OBP-801 induced <i>NOXA</i> expression and caspase-dependent apoptosis in rhabdoid tumor cell lines independent of TP53. Chromatin immunoprecipitation assay showed that OBP-801 acetylated histone proteins and recruited RNA polymerase II to the transcription start site (TSS) of the <i>NOXA</i> promotor. Moreover, OBP-801 recruited BRG1 and BAF155, which are members of the SWI/SNF complex, to the TSS of the <i>NOXA</i> promotor. These results suggest that OBP-801 epigenetically releases the silencing of <i>NOXA</i> and induces apoptosis in rhabdoid tumors. OBP-801 strongly inhibited tumor growth in human rhabdoid tumor xenograft mouse models <i>in vivo</i> Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and cleaved caspase-3 were stained in tumors treated with OBP-801. In conclusion, OBP-801 induces apoptosis in rhabdoid tumor cells by epigenetically releasing the silencing of <i>NOXA</i>, which is a key mediator of rhabdoid tumor apoptosis. The epigenetic approach for <i>NOXA</i> silencing with OBP-801 is promising for rhabdoid tumor treatment.