当前位置: X-MOL 学术Sci. Signal. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
The HDAC3–SMARCA4–miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma
Science Signaling ( IF 6.7 ) Pub Date : 2018-11-20 , DOI: 10.1126/scisignal.aau7632
Narendra Bharathy 1 , Noah E. Berlow 1 , Eric Wang 2 , Jinu Abraham 3 , Teagan P. Settelmeyer 1 , Jody E. Hooper 4 , Matthew N. Svalina 1 , Yoshihiro Ishikawa 5 , Keith Zientek 5 , Zia Bajwa 1, 6 , Martin W. Goros 7 , Brian S. Hernandez 7 , Johannes E. Wolff 8 , Michelle A. Rudek 9, 10, 11 , Linping Xu 9, 10 , Nicole M. Anders 9, 10 , Ranadip Pal 12 , Alexandria P. Harrold 1 , Angela M. Davies 13 , Arya Ashok 13 , Darnell Bushby 13 , Maria Mancini 13 , Christopher Noakes 13 , Neal C. Goodwin 13 , Peter Ordentlich 14 , James Keck 15 , Douglas S. Hawkins 16 , Erin R. Rudzinski 16 , Bishwanath Chatterjee 17 , Hans Peter Bächinger 5, 18 , Frederic G. Barr 17 , Jennifer Liddle 19 , Benjamin A. Garcia 19 , Atiya Mansoor 6 , Theodore J. Perkins 20, 21 , Christopher R. Vakoc 2 , Joel E. Michalek 7 , Charles Keller 1
Affiliation  

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. This reexpression of miR-27a led to PAX3:FOXO1 mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase 1 clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase 1B cohort expansion or phase 2 clinical trials. Together, these results implicate an HDAC3–SMARCA4–miR-27a–PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients.



中文翻译:

HDAC3–SMARCA4–miR-27a轴促进横纹肌肉瘤中PAX3:FOXO1融合癌基因的表达

横纹肌肉瘤(RMS)是儿童最常见的软组织肉瘤,数十年来一直未满足临床需求。单个致癌融合基因与治疗耐药性相关,总生存期降低40%至45%。先前我们显示了此PAX3:FOXO1的表达肺泡RMS(aRMS)中的融合癌基因介导了对化学疗法和放射疗法的耐受性,并且I类特异性组蛋白脱乙酰基酶(HDAC)抑制剂恩替司他降低了PAX3:FOXO1蛋白的丰度。在这里,我们建立了恩替司他化学疗法在各种临床前细胞和小鼠模型中的抗肿瘤功效,并发现HDAC3抑制是恩替司他诱导的PAX3:FOXO1丰度抑制的主要机制。恩替司他对HDAC3的抑制作用会降低染色质重塑酶SMARCA4的活性,进而降低microRNA miR-27a的表达。miR-27a的这种重新表达导致PAX3:FOXO1培养和体内aRMS细胞中的mRNA失稳和化学疗法致敏作用。此外,一项1期临床试验(ADVL1513)已显示恩替司他对患有复发性或难治性实体瘤的儿童具有耐受性,并计划用于1B期人群扩展或2期临床试验。总之,这些结果暗示着HDAC3–SMARCA4–miR-27a–PAX3:FOXO1回路是抗化学性aRMS的驱动器,并表明用恩替司他靶向该途径可能对患者具有治疗效果。

更新日期:2018-11-21
down
wechat
bug