St. Jude Reference #SJ-17-0030
Description
Researchers at St. Jude were drawn to investigate CXorf67 because they found recurrent mutations in the gene in some posterior fossa ependymomas. The researchers discovered a potential mechanism of epigenetic regulation involving CXorf67, a gene of previous unknown function. CXorf67 is overexpressed in some tumors, notably ependymomas and germinomas. The researchers also found the protein product of CXorf67 is bound to three core proteins, EZH2, SUZ12, and EED, of the PRC2 complex, which modifies regulatory sites on histones, particularly methylation of H3 K27. Since this CXorf67 discovery, the corresponding literature generated has popularized the synonymous name EZHIP (Enhancer of Zeste Homologs Inhibitory Protein).
It is increasingly appreciated that (i) histone modifications are important in the regulation of gene expression and that (ii) PRC2, one of the polycomb group (PcG) proteins, is in turn an important regulator of histone modifications. Researchers at St. Jude are continuing their work to better understand such functions for a range of diseases, including cancer, where histone modifications pathologically alter epigenetic regulation. There may be multiple potential applications for manipulating this mechanism with pharmacologic compounds based upon the structure of CXorf67 or upon the way in which it functions.
Keywords
EZHIP, Ependymoma, Germinoma, Molecular heterogeneity, DNA methylation profiling, CXorf67, PRC2, H3 K27M, H3 K27-trimethylation
Granted patents or published applications
Pending US patent application published as 2021/0363587. PCT previously published as WO 2019/155387
Related scientific references
Kristian W. Pajtler, Ji Wen, Martin Sill, Tong Lin, Wilda Orisme, Bo Tang, Jens‑Martin Hübner, Vijay Ramaswamy, Sujuan Jia, James D. Dalton, Kelly Haupfear, Hazel A. Rogers, Chandanamali Punchihewa, Ryan Lee, John Easton, Gang Wu, Timothy A. Ritzmann, Rebecca Chapman, Lukas Chavez, Fredrick A. Boop, Paul Klimo, Noah D. Sabin, Robert Ogg, Stephen C. Mack, Brian D. Freibaum, Hong Joo Kim, Hendrik Witt, David T. W. Jones, Baohan Vo, Amar Gajjar, Stan Pounds, Arzu Onar‑Thomas, Martine F. Roussel, Jinghui Zhang, J. Paul Taylor, Thomas E. Merchant, Richard Grundy, Ruth G. Tatevossian, Michael D. Taylor, Stefan M. Pfister, Andrey Korshunov, Marcel Kool, David W. Ellison. Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA). Acta Neuropathologica. 10 June 2018. https://doi.org/10.1007/s00401-018-1877-0
Anne Jenseit, Aylin Camgöz, Stefan M. Pfister, Marcel Kool, EZHIP: a new piece of the puzzle towards understanding pediatric posterior fossa ependymoma, Acta Neuropathologica, November, 2021. https://doi.org/10.1007/s00401-021-02382-4
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