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Statins repress hedgehog signaling in medulloblastoma with no bone toxicities

Abstract

The Hedgehog (Hh) pathway plays an indispensable role in bone development and genetic activation of the pathway results in medulloblastoma (MB), the most common malignant brain tumor in children. Inhibitors of Hh pathway (such as vismodegib and sonedigib), which are used to treat MB, cause irreversible defects in bone growth in young children. Cholesterol is required for the activation of the Hh pathway, and statins, inhibitors of cholesterol biosynthesis, suppress MB growth by repressing Hh signaling in tumor cells. Here, we investigate the role of cholesterol biosynthesis in the proliferation and Hh signaling in chondrocytes, and examine the bone development in mice after statin treatment. Statins significantly inhibited MB growth in young mice, but caused no defects in bone development. Conditional deletion of NADP steroid dehydrogenase-like (NSDHL), an enzyme necessary for cholesterol biosynthesis, suppressed cholesterol synthesis in chondrocytes, and disrupted the growth plate in mouse femur and tibia, indicating the important function of intracellular cholesterol in bone development. Hh pathway activation and the proliferation of chondrocytes were inhibited by statin treatment in vitro; however, statins did not impair bone growth in vivo due to insufficient penetration into the bone. Our studies reveal a critical role of cholesterol in bone development, and support the utilization of statins for treatment of MB as well as other Hh pathway-associated malignancies.

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Fig. 1: Simvastatin inhibited the proliferation and Hh signaling in MB cells.
Fig. 2: Statins synergized with vismodegib in inhibiting MB cell proliferation.
Fig. 3: No bone defects were detected in mice after simvastatin treatment.
Fig. 4: Statins inhibited chondrocyte proliferation in vitro.
Fig. 5: Deficiency in cholesterol biosynthesis inhibited chondrocyte proliferation.
Fig. 6: Penetration of simvastatin in brain and bone.

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Acknowledgements

We would like to thank Drs. Andrey Efimov, Kathy Cai, Dusica Cvetkovic, and James Oesterling for technical assistance; and Drs. Maike Sander, Joan Font-Burgada, and Sergei Grivenniko for providing transgenic mice. This research was supported by American Cancer Society (RSG1605301NEC to Z.-j.Y.), American Brain Tumor Association (DG1900025 to Z.-j.Y.), PA CURE Health Research Fund (CURE 4100068716 to Z.-j.Y.), National Natural Science Foundation of China (81803616 to C.Z.), and the Natural Science Foundation of Jiangsu Higher Education Institutions (18KJB350010 to C.Z.).

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Fan, Q., Gong, T., Zheng, C. et al. Statins repress hedgehog signaling in medulloblastoma with no bone toxicities. Oncogene 40, 2258–2272 (2021). https://doi.org/10.1038/s41388-021-01701-z

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