Deogharkar Akash, Singh Satishkumar Vishram, Bharambe Harish Shrikrishna, Paul Raikamal, Moiyadi Aliasgar, Goel Atul, Shetty Prakash, Sridhar Epari, Gupta Tejpal, Jalali Rakesh, Goel Naina, Gadewal Nikhil, Muthukumar Sahana, Shirsat Neelam Vishwanath
Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India.
Homi Bhabha National Institute, Mumbai, Maharashtra 400094, India.
Hum Mol Genet. 2021 Aug 28;30(18):1721-1733. doi: 10.1093/hmg/ddab134.
Medulloblastoma, a common pediatric malignant brain tumor, consists of four distinct molecular subgroups WNT, SHH, Group 3 and Group 4. Exome sequencing of 11 WNT subgroup medulloblastomas from an Indian cohort identified mutations in several chromatin modifier genes, including genes of the mammalian SWI/SNF complex. The genome of WNT subgroup tumors is known to be stable except for monosomy 6. Two tumors, having monosomy 6, carried a loss of function mutation in the ARID1B gene located on chromosome 6. ARID1B expression is also lower in the WNT subgroup tumors compared to other subgroups and normal cerebellar tissues that could result in haploinsufficiency. The short hairpin RNA-mediated knockdown of ARID1B expression resulted in a significant increase in the malignant potential of medulloblastoma cells. Transcriptome sequencing identified upregulation of several genes encoding cell adhesion proteins, matrix metalloproteases indicating the epithelial-mesenchymal transition. The ARID1B knockdown also upregulated ERK1/ERK2 and PI3K/AKT signaling with a decrease in the expression of several negative regulators of these pathways. The expression of negative regulators of the WNT signaling like TLE1, MDFI, GPX3, ALX4, DLC1, MEST decreased upon ARID1B knockdown resulting in the activation of the canonical WNT signaling pathway. Synthetic lethality has been reported between SWI/SNF complex mutations and EZH2 inhibition, suggesting EZH2 inhibition as a possible therapeutic modality for WNT subgroup medulloblastomas. Thus, the identification of ARID1B as a tumor suppressor and its downregulation resulting in the activation of multiple signaling pathways opens up opportunities for novel therapeutic modalities for the treatment of WNT subgroup medulloblastoma.
髓母细胞瘤是一种常见的儿童恶性脑肿瘤，由四个不同的分子亚组组成，即WNT、SHH、3组和4组。对来自印度队列的11个WNT亚组髓母细胞瘤进行外显子组测序，发现了几个染色质修饰基因的突变，包括哺乳动物SWI/SNF复合体的基因。已知WNT亚组肿瘤的基因组除了6号染色体单体性外是稳定的。两个具有6号染色体单体性的肿瘤在位于6号染色体上的ARID1B基因中携带功能丧失突变。与其他亚组和正常小脑组织相比，WNT亚组肿瘤中的ARID1B表达也较低，这可能导致单倍剂量不足。短发夹RNA介导的ARID1B表达敲低导致髓母细胞瘤细胞的恶性潜能显著增加。转录组测序确定了几个编码细胞粘附蛋白、基质金属蛋白酶的基因上调，表明上皮-间质转化。ARID1B敲低还上调了ERK1/ERK2和PI3K/AKT信号通路，同时这些通路的几个负调节因子的表达下降。ARID1B敲低后，WNT信号通路的负调节因子如TLE1、MDFI、GPX3、ALX4、DLC1、MEST的表达下降，导致经典WNT信号通路的激活。据报道，SWI/SNF复合体突变与EZH2抑制之间存在合成致死性，这表明EZH2抑制可能是WNT亚组髓母细胞瘤的一种治疗方式。因此，将ARID1B鉴定为肿瘤抑制因子及其下调导致多种信号通路的激活，为WNT亚组髓母细胞瘤的治疗开辟了新的治疗方式机会。
