The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma.

The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma. Sci Signal. 2018 Nov 20;11(557): Authors: Bharathy N, Berlow NE, Wang E, Abraham J, Settelmeyer TP, Hooper JE, Svalina MN, Ishikawa Y, Zientek K, Bajwa Z, Goros MW, Hernandez BS, Wolff JE, Rudek MA, Xu L, Anders NM, Pal R, Harrold AP, Davies AM, Ashok A, Bushby D, Mancini M, Noakes C, Goodwin NC, Ordentlich P, Keck J, Hawkins DS, Rudzinski ER, Chatterjee B, Bächinger HP, Barr FG, Liddle J, Garcia BA, Mansoor A, Perkins TJ, Vakoc CR, Michalek JE, Keller C Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. We previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I-specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, we established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance. HDAC3 inhibition by entinostat decreased the activity of the chromatin remodeling enzyme SMARCA4, which, in turn, derepressed the microRNA miR-27a. ...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research