TY - JOUR
T1 - Targeting cyclin-dependent kinase 9 sensitizes medulloblastoma cells to chemotherapy
AU - Song, Heyu
AU - Bhakat, Reeyan
AU - Kling, Matthew J.
AU - Coulter, Donald W.
AU - Chaturvedi, Nagendra K.
AU - Ray, Sutapa
AU - Joshi, Shantaram S.
N1 - Funding Information:
The authors thank Fred & Pamela Buffett Cancer Center Support Grant (P30CA036727), Pediatric Cancer Research Group Support, State of Nebraska, LB905 (to DC). H Song is supported by UNMC graduate assistant fellowship. The authors thank the UNMC tissue science core facilities for IHC analysis.
Funding Information:
The authors thank Fred & Pamela Buffett Cancer Center Support Grant ( P30CA036727 ), Pediatric Cancer Research Group Support, State of Nebraska, LB905 (to DC). H Song is supported by UNMC graduate assistant fellowship . The authors thank the UNMC tissue science core facilities for IHC analysis.
Publisher Copyright:
© 2019 The Authors
PY - 2019/12/3
Y1 - 2019/12/3
N2 - Medulloblastoma (MB) is a highly aggressive, malignant brain tumor in children with poor prognosis. Cyclin-dependent kinase 9 (CDK9), a serine-threonine kinase, is widely implicated in the control of basal gene expression by phosphorylating Serine 2 (Ser2) of the heptad repeat in the RNA Polymerase II (RNA Pol II) C-terminal domain (CTD). Although CDK9 plays a pathogenic role in various cancers, its function in MB remains unknown. Here, we show that CDK9 is highly expressed in MB tumors and increased CDK9 expression is correlated with high risk MB patients. CDK9 expression along with phospho-Ser2 RNA Pol II (pRNA Pol II ser2) and bromodomain-binding protein 4 (BRD4), which recruits CDK9, were elevated in multiple MB cell lines and in MB tumors originated spontaneously from Ptch1+/− p53−/− mice. Inhibition of CDK9 with LDC067 suppressed MB cell growth, reduced pRNA Pol II ser2 level and expression of oncogenic markers, including MYC. Moreover, LDC067 treatment synergistically sensitizes MB cells to chemotherapeutic agent cisplatin. Further, LDC067 in combination with BRD4 inhibitor decreased MB cells growth, delayed cell migration and attenuated pRNA Pol II ser2 occupancy to CCND1 and BCL2 gene promoters as revealed by chromatin immunoprecipitation assay (ChIP). Together, these findings highlight the importance of CDK9 in MB pathogenesis and suggest that it may serve as a promising therapeutic target for the treatment of MB.
AB - Medulloblastoma (MB) is a highly aggressive, malignant brain tumor in children with poor prognosis. Cyclin-dependent kinase 9 (CDK9), a serine-threonine kinase, is widely implicated in the control of basal gene expression by phosphorylating Serine 2 (Ser2) of the heptad repeat in the RNA Polymerase II (RNA Pol II) C-terminal domain (CTD). Although CDK9 plays a pathogenic role in various cancers, its function in MB remains unknown. Here, we show that CDK9 is highly expressed in MB tumors and increased CDK9 expression is correlated with high risk MB patients. CDK9 expression along with phospho-Ser2 RNA Pol II (pRNA Pol II ser2) and bromodomain-binding protein 4 (BRD4), which recruits CDK9, were elevated in multiple MB cell lines and in MB tumors originated spontaneously from Ptch1+/− p53−/− mice. Inhibition of CDK9 with LDC067 suppressed MB cell growth, reduced pRNA Pol II ser2 level and expression of oncogenic markers, including MYC. Moreover, LDC067 treatment synergistically sensitizes MB cells to chemotherapeutic agent cisplatin. Further, LDC067 in combination with BRD4 inhibitor decreased MB cells growth, delayed cell migration and attenuated pRNA Pol II ser2 occupancy to CCND1 and BCL2 gene promoters as revealed by chromatin immunoprecipitation assay (ChIP). Together, these findings highlight the importance of CDK9 in MB pathogenesis and suggest that it may serve as a promising therapeutic target for the treatment of MB.
KW - BRD4
KW - CDK9
KW - Cisplatin
KW - Medulloblastoma
KW - P-TEFb
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U2 - 10.1016/j.bbrc.2019.09.118
DO - 10.1016/j.bbrc.2019.09.118
M3 - Article
C2 - 31594641
AN - SCOPUS:85073025421
SN - 0006-291X
VL - 520
SP - 250
EP - 256
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -