Wynn Daniel T, Rodriguez-Blanco Jezabel, Long Jun, Yang Fan, Shen Chen, Fei Dennis, Tang Hsin-Yao, Hanson Derek, Robbins David J
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA.
Neurooncol Adv. 2022 Sep 29;4(1):vdac144. doi: 10.1093/noajnl/vdac144. eCollection 2022 Jan-Dec.
Medulloblastoma (MB) is the most common pediatric brain tumor. Although standard-of-care treatment generally results in good prognosis, many patients exhibit treatment-associated lifelong disabilities. This outcome could be improved by employing therapies targeting the molecular drivers of this cancer. Attempts to do so in the SONIC HEDGEHOG MB subgroup (SHH-MB) have largely focused on the SHH pathway's principal activator, smoothened (SMO). While inhibitors targeting SMO have shown clinical efficacy, recurrence and resistance are frequently noted, likely resulting from mutations in or downstream of SMO. Therefore, identification of novel SHH regulators that act on the pathway's terminal effectors could be used to overcome or prevent such recurrence. We hypothesized that protein arginine methyltransferase 5 (PRMT5) is one such regulator and investigated its role and potential targeting in SHH-MB.
PRMT5 expression in SHH-MB was first evaluated. Knockdown and pharmacological inhibitors of PRMT5 were used in SHH-MB sphere cultures to determine its effect on viability and SHH signaling. GLI1 arginine methylation was then characterized in primary SHH-MB tissue using LC-MS/MS. Finally, PRMT5 inhibitor efficacy was evaluated
PRMT5 is overexpressed in SHH-MB tissue. Furthermore, SHH-MB viability and SHH activity is dependent on PRMT5. We found that GLI1 isolated from SHH-MB tissues is highly methylated, including three PRMT5 sites that affect SHH-MB cell viability. Importantly, tumor growth is decreased and survival increased in mice given PRMT5 inhibitor.
PRMT5 is a requisite driver of SHH-MB that regulates tumor progression. A clinically relevant PRMT5 inhibitor represents a promising candidate drug for SHH-MB therapy.
髓母细胞瘤（MB）是最常见的儿童脑肿瘤。尽管标准治疗通常能带来良好的预后，但许多患者会出现与治疗相关的终身残疾。通过采用针对这种癌症分子驱动因素的疗法，这一结果可能会得到改善。在音猬因子髓母细胞瘤亚组（SHH-MB）中尝试这样做主要集中在SHH信号通路的主要激活剂—— smoothened（SMO）上。虽然靶向SMO的抑制剂已显示出临床疗效，但复发和耐药现象经常出现，这可能是由于SMO或其下游的突变所致。因此，鉴定作用于该信号通路终末效应器的新型SHH调节剂可用于克服或预防此类复发。我们假设蛋白质精氨酸甲基转移酶5（PRMT5）就是这样一种调节剂，并研究了其在SHH-MB中的作用和潜在靶向性。
首先评估PRMT5在SHH-MB中的表达。在SHH-MB球状体培养物中使用PRMT5的敲低和药理抑制剂来确定其对活力和SHH信号传导的影响。然后使用液相色谱-串联质谱法（LC-MS/MS）在原发性SHH-MB组织中对GLI1精氨酸甲基化进行表征。最后，评估PRMT5抑制剂的疗效。
PRMT5在SHH-MB组织中过表达。此外，SHH-MB的活力和SHH活性依赖于PRMT5。我们发现从SHH-MB组织中分离出的GLI1高度甲基化，包括三个影响SHH-MB细胞活力的PRMT5位点。重要的是，给予PRMT5抑制剂的小鼠肿瘤生长减缓且生存期延长。
PRMT5是调节肿瘤进展的SHH-MB必需驱动因子。一种具有临床相关性的PRMT5抑制剂是SHH-MB治疗的有前景的候选药物。
