Hedgehog signaling drives medulloblastoma growth via CDK6
David R. Raleigh, Pervinder K. Choksi, Alexis Leigh Krup, Wasima Mayer, Nicole Santos, Jeremy F. Reiter
David R. Raleigh, Pervinder K. Choksi, Alexis Leigh Krup, Wasima Mayer, Nicole Santos, Jeremy F. Reiter
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Concise Communication Oncology

Hedgehog signaling drives medulloblastoma growth via CDK6

Abstract

Medulloblastoma, an aggressive cancer of the cerebellum, is among the most common pediatric brain tumors. Approximately one-third of medulloblastomas are associated with misactivation of the Hedgehog (Hh) pathway. GLI family zinc finger 2 (GLI2) coordinates the Hh transcriptional program; however, the GLI2 targets that promote cancer cell proliferation are unknown. Here, we incorporated a Gli2-EGFP allele into 2 different genetic mouse models of Hh-associated medulloblastoma. Hh signaling induced GLI2 binding to the Cdk6 promoter and activated Cdk6 expression, thereby promoting uncontrolled cell proliferation. Genetic or pharmacological inhibition of CDK6 in mice repressed the growth of Hh-associated medulloblastoma and prolonged survival through inhibition of cell proliferation. In human medulloblastoma, misactivation of Hh signaling was associated with high levels of CDK6, pointing to CDK6 as a direct transcriptional target of the Hh pathway. These results suggest that CDK6 antagonists may be a promising therapeutic approach for Hh-associated medulloblastoma in humans.

Authors

David R. Raleigh, Pervinder K. Choksi, Alexis Leigh Krup, Wasima Mayer, Nicole Santos, Jeremy F. Reiter

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Figure 3

Inhibition of CDK6 attenuates Hh-associated medulloblastoma growth.

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Inhibition of CDK6 attenuates Hh-associated medulloblastoma growth. (A) ...
(A) Cerebella weight normalized to total brain weight from P35 mice (SmoM2c [n = 12, white], Math1-Cre SmoM2c [n = 12, gray], Math1-Cre SmoM2c Cdk6KO/+ [n = 7, light blue], and Math1-Cre SmoM2c Cdk6KO/KO [n = 19, dark blue]) and P35 mice treated with pharmacologic agents (Math1-Cre SmoM2c with vismodegib 75 μg/g [n = 15, black], vismodegib 100 μg/g [n = 14, black], palbociclib 50 μg/g [n = 11, green], palbociclib 100 μg/g [n = 12, green], or vismodegib 75 μg/g, and palbociclib 50 μg/g [n = 13, orange], and Math1-Cre SmoM2c Cdk6KO/KO with palbociclib 100 μg/g [n = 6, blue]). P < 0.04, t test. (B) P35 sagittal midline cerebellar H&E light micrographs. Scale bar: 1 mm (representative of 3 experiments). (C) Kaplan-Meier curves of 20 Math1-Cre SmoM2c (gray), 24 Math1-Cre SmoM2c Cdk6KO/+ (light blue), and 25 Math1-Cre SmoM2c Cdk6KO/KO mice. P < 0.0001, log-rank test. (D) Kaplan-Meier curves of 13 Math1-Cre Ptch1c/c Cdk6+/+ (gray), 10 Math1-Cre Ptch1c/c Cdk6KO/KO (blue), and 8 Math1-Cre Ptch1c/c Cdk6+/+ mice treated with 100 μg/g palbociclib from P21 until death (green). P < 0.0001, log-rank test. (E) P35 brain micrographs. Scale bar: 5 mm (representative of 3 experiments). (F) Cerebella weight normalized to total brain weight of P35 mice, including 12 Ptch1c/c (white), 12 Math1-Cre Ptch1c/c (gray), and Math1-Cre Ptch1c/c, treated with 75 μg/g abemaciclib (n = 8, light green) or 100 μg/g palbociclib (n = 11, green). (G) BrdU quantification of Math1-Cre SmoM2c medulloblastomas. P < 0.03, t test. n = 3. (H) qRT-PCR of DAOY, D283, and D341 cells. P < 0.05, t test. n = 3. (I) Ki-67 quantification in DAOY, D283, and D341 cells. *P < 0.05, t test. n = 6.