Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability
Year: 2023
Type: article
Abstract: MYC-driven medulloblastomas are highly aggressive childhood brain tumors, however, the molecular and genetic events triggering MYC amplification and malignant transformation remain elusive. Here we report that mutations in CTDNEP1, a CTD nuclear-envelope-phosphatase, are the most significantly enriched recurrent alterations in MYC-driven medulloblastomas, and define high-risk subsets with poorer prognosis. Ctdnep1 ablation promotes the transformation of murine cerebellar progenitors into Myc-amplified medulloblastomas, resembling their human counterparts. CTDNEP1 deficiency stabilizes and activates MYC activity by elevating MYC serine-62 phosphorylation, and triggers chromosomal instability to induce p53 loss and Myc amplifications. Further, phosphoproteomics reveals that CTDNEP1 post-translationally modulates the activities of key regulators for chromosome segregation and mitotic checkpoint regulators including topoisomerase TOP2A and checkpoint kinase CHEK1. Co-targeting MYC and CHEK1 activities synergistically inhibits CTDNEP1-deficient MYC-amplified tumor growth and prolongs animal survival. Together, our studies demonstrate that CTDNEP1 is a tumor suppressor in highly aggressive MYC-driven medulloblastomas by controlling MYC activity and mitotic fidelity, pointing to a CTDNEP1-dependent targetable therapeutic vulnerability.
Source: Nature Communications
Authors: Zaili Luo, Yunfei Liao, Dazhuan Xin, Kalen Berry, Sean Ogurek, Xinran Dong, Hao Li, Jianzhong Yu, Feng Zhang, Ron Han, Chen Dong, Mingyang Xia, Lingli Xu, Yifeng Lin, Chang Ye, Liguo Zhang, Guoying Huang, Wenhao Zhou, Mei Xin, xiaohua hu, Chuntao Zhao, Rohit Rao, Ryuichi Nishinakamura, Jiyang Yu, Marcel Kool, Stefan Pfister, Martine Roussel, William A Weiss, Paul Andreassen, Q. Richard Lu
Institutions: Cincinnati Children's Hospital Medical Center, Fudan University, Children's Hospital of Fudan University, St. Jude Children's Research Hospital, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto University, German Cancer Research Center, Hopp Children's Cancer Center Heidelberg, Deutsches Konsortium für Translationale Krebsforschung, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center, University of Cincinnati
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,290
OpenAlex ID: W4319946489