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Presentation date

Summer 8-12-2021

College, Institute, or Department

Pediatrics

Faculty Mentor

Sutapa Ray

Research Mentor

Sutapa Ray

Abstract

Medulloblastoma (MB) is the most common primary malignant brain tumor of childhood. The current treatment options for MB patients involves combination of surgical resection followed by high doses of radiation and chemotherapy. However, these therapies are associated with risk for recurrence and serious neuro-cognitive and endocrine sequelae, thereby warranting the immediate need of better treatment options. Our previous study showed that Signal Transducer and Activator of Transcription factor-3 (STAT3) and Cyclin dependent Kinase -9 (CDK9) are overexpressed in MB and are correlated with poor prognosis. CDK9, an important regulator of transcriptional elongation, is a major component of a complex known as the positive transcriptional elongation factor b (P-TEFb). P-TEFb activates RNA Pol II by phosphorylating negative elongation factors and serine 2 (Ser2) of the heptad repeat in the Pol II C-terminal domain (CTD) and thereby transitioning paused RNA polymerase II to enter a productive transcriptional elongation mode. Both STAT3 and CDK9 are considered as promising targets for cancer therapy, particularly for cancers driven by transcriptional dysregulation. In this study, we aim to elucidate the role of CDK9 in STAT3-mediated MB pathogenies. We have determined that CDK9 physically interacts with STAT3 in HD-MB03 (MYC-driven Group 3) and ONS-76 (SHH) MB cells. We observed that pharmacologic inhibition of CDK9 with Flavopiridol(FP) in STAT3 knockdown (KD) MB cells significantly decreases cell viability. Furthermore, combination of STAT3 KD and FP treatment decreases protein expression of MYC and increases cleaved PARP, indicating its effect on inhibition of proliferation and induction of apoptosis respectively. Combination of STAT3 KD and FP treatment also decreases pSer2RNA Pol II expression, indicating inhibition of transcription elongation of a subset of STAT3 target genes. Therefore, the STAT3-CDK9 axis may serve as a potential therapeutic target in the treatment of pediatric MB.

Keywords

Medulloblastoma, Signal Transducer and Activator of Transcription factor-3, Cyclin dependent Kinase-9

Functional Role of STAT3-CDK9 Complex in Medulloblastoma Pathogenesis

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