STAT3 Inhibition Attenuates MYC Expression by Modulating Co-Activator Recruitment and Suppresses Medulloblastoma Tumor Growth by Augmenting Cisplatin Efficacy In Vivo

SIMPLE SUMMARY: Medulloblastoma (MB) is a malignant brain tumor of childhood that occurs in the cerebellum and accounts for 20–25% of all pediatric central nervous system tumors. Despite improvement in overall survival rate, it still lacks an effective targeted treatment strategy. Here, we delineated mechanistically the functional role of activated signal transducers and activators of transcription-3 (STAT3) in the expression of oncogenic targets MYC, and in promoting MB tumorigenesis and chemoresistance. We validated the in vitro and in vivo efficacy of inhibiting STAT3 by genetic and pharmacologic inhibition in combination with chemotherapy in subcutaneous and orthotopic mouse models of MB. STAT3 inhibitors, along with chemotherapy, may serve as a novel therapeutic strategy, improving outcomes and the quality of life in pediatric MB patients. ABSTRACT: 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.