Rohrer Kyle A, Song Heyu, Akbar Anum, Chen Yingling, Pramanik Suravi, Wilder Phillip J, McIntyre Erin M, Chaturvedi Nagendra K, Bhakat Kishor K, Rizzino Angie, Coulter Don W, Ray Sutapa
Department of Pediatrics, Hematology and Oncology Division, Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Cancers (Basel). 2023 Apr 11;15(8):2239. doi: 10.3390/cancers15082239.
MB is a common childhood malignancy of the central nervous system, with significant morbidity and mortality. Among the four molecular subgroups, MYC-amplified Group 3 MB is the most aggressive type and has the worst prognosis due to therapy resistance. The present study aimed to investigate the role of activated STAT3 in promoting MB pathogenesis and chemoresistance via inducing the cancer hallmark MYC oncogene. Targeting STAT3 function either by inducible genetic knockdown (KD) or with a clinically relevant small molecule inhibitor reduced tumorigenic attributes in MB cells, including survival, proliferation, anti-apoptosis, migration, stemness and expression of MYC and its targets. STAT3 inhibition attenuates MYC expression by affecting recruitment of histone acetyltransferase p300, thereby reducing enrichment of H3K27 acetylation in the MYC promoter. Concomitantly, it also decreases the occupancy of the bromodomain containing protein-4 (BRD4) and phosphoSer2-RNA Pol II (pSer2-RNAPol II) on MYC, resulting in reduced transcription. Importantly, inhibition of STAT3 signaling significantly attenuated MB tumor growth in subcutaneous and intracranial orthotopic xenografts, increased the sensitivity of MB tumors to cisplatin, and improved the survival of mice bearing high-risk MYC-amplified tumors. Together, the results of our study demonstrate that targeting STAT3 may be a promising adjuvant therapy and chemo-sensitizer to augment treatment efficacy, reduce therapy-related toxicity and improve quality of life in high-risk pediatric patients.
髓母细胞瘤（MB）是儿童常见的中枢神经系统恶性肿瘤，具有较高的发病率和死亡率。在四个分子亚组中，MYC扩增的3型MB是最具侵袭性的类型，由于对治疗耐药，其预后最差。本研究旨在探讨激活的信号转导和转录激活因子3（STAT3）通过诱导癌症标志性MYC癌基因在促进MB发病机制和化疗耐药中的作用。通过诱导性基因敲低（KD）或使用临床相关的小分子抑制剂靶向STAT3功能，可降低MB细胞的致瘤特性，包括存活、增殖、抗凋亡、迁移、干性以及MYC及其靶点的表达。STAT3抑制通过影响组蛋白乙酰转移酶p300的募集来减弱MYC表达，从而减少MYC启动子中H3K27乙酰化的富集。同时，它还降低了含溴结构域蛋白4（BRD4）和磷酸化丝氨酸2-RNA聚合酶II（pSer2-RNAPol II）在MYC上的占有率，导致转录减少。重要的是，抑制STAT3信号显著减弱了皮下和颅内原位异种移植瘤中MB的肿瘤生长，增加了MB肿瘤对顺铂的敏感性，并提高了携带高危MYC扩增肿瘤小鼠的存活率。总之，我们的研究结果表明，靶向STAT3可能是一种有前景的辅助治疗和化疗增敏剂，可提高治疗效果，降低治疗相关毒性，并改善高危儿科患者的生活质量。
