PMID- 37190167 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230519 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 15 IP - 8 DP - 2023 Apr 11 TI - STAT3 Inhibition Attenuates MYC Expression by Modulating Co-Activator Recruitment and Suppresses Medulloblastoma Tumor Growth by Augmenting Cisplatin Efficacy In Vivo. LID - 10.3390/cancers15082239 [doi] LID - 2239 AB - 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. FAU - Rohrer, Kyle A AU - Rohrer KA AD - Department of Pediatrics, Hematology and Oncology Division, Nebraska Medical Center, Omaha, NE 68198, USA. FAU - Song, Heyu AU - Song H AD - Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA. AD - Department of Medicine, University of Arizona, Tucson, AZ 85721, USA. FAU - Akbar, Anum AU - Akbar A AUID- ORCID: 0000-0001-8439-7671 AD - Department of Pediatrics, Hematology and Oncology Division, Nebraska Medical Center, Omaha, NE 68198, USA. AD - Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA. FAU - Chen, Yingling AU - Chen Y AD - Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA. FAU - Pramanik, Suravi AU - Pramanik S AUID- ORCID: 0000-0001-9166-3085 AD - Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA. FAU - Wilder, Phillip J AU - Wilder PJ AD - Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE 68198, USA. FAU - McIntyre, Erin M AU - McIntyre EM AD - Department of Pediatrics, Hematology and Oncology Division, Nebraska Medical Center, Omaha, NE 68198, USA. AD - Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA. FAU - Chaturvedi, Nagendra K AU - Chaturvedi NK AUID- ORCID: 0000-0001-7037-898X AD - Department of Pediatrics, Hematology and Oncology Division, Nebraska Medical Center, Omaha, NE 68198, USA. AD - Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA. AD - Fred & Pamela Buffett Cancer Center, Omaha, NE 68198, USA. FAU - Bhakat, Kishor K AU - Bhakat KK AD - Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA. AD - Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA. AD - Fred & Pamela Buffett Cancer Center, Omaha, NE 68198, USA. FAU - Rizzino, Angie AU - Rizzino A AD - Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA. AD - Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE 68198, USA. AD - Fred & Pamela Buffett Cancer Center, Omaha, NE 68198, USA. FAU - Coulter, Don W AU - Coulter DW AUID- ORCID: 0000-0002-7829-0971 AD - Department of Pediatrics, Hematology and Oncology Division, Nebraska Medical Center, Omaha, NE 68198, USA. AD - Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA. AD - Fred & Pamela Buffett Cancer Center, Omaha, NE 68198, USA. FAU - Ray, Sutapa AU - Ray S AUID- ORCID: 0000-0003-4234-2124 AD - Department of Pediatrics, Hematology and Oncology Division, Nebraska Medical Center, Omaha, NE 68198, USA. AD - Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA. AD - Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE 68198, USA. LA - eng GR - LB506/Child Health Research Institute/Pediatric Cancer Research, Team Jack Foundation, Edna Ittner Pediatric Research Support/ PT - Journal Article DEP - 20230411 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC10136921 OTO - NOTNLM OT - H3K27Ac OT - MYC OT - STAT3 OT - chemoresistance OT - medulloblastoma OT - p300 COIS- The authors declare no conflict of interest. EDAT- 2023/05/16 06:42 MHDA- 2023/05/16 06:43 PMCR- 2023/04/11 CRDT- 2023/05/16 01:13 PHST- 2023/02/22 00:00 [received] PHST- 2023/04/05 00:00 [revised] PHST- 2023/04/07 00:00 [accepted] PHST- 2023/05/16 06:43 [medline] PHST- 2023/05/16 06:42 [pubmed] PHST- 2023/05/16 01:13 [entrez] PHST- 2023/04/11 00:00 [pmc-release] AID - cancers15082239 [pii] AID - cancers-15-02239 [pii] AID - 10.3390/cancers15082239 [doi] PST - epublish SO - Cancers (Basel). 2023 Apr 11;15(8):2239. doi: 10.3390/cancers15082239.