Research progress on the function and mechanism of CXorf67 in PFA ependymoma

Abstract

<p indent="0mm">CXorf6 (chromosome X open reading frame 67) protein contains 503 amino acids and is predicted <italic>in silico</italic> to be mostly disordered. <italic>CXorf6</italic>7 is barely expressed in most cell lines and human tissues. Therefore, for rather a long time, our understandings regarding functions of this protein are quite limited. In 2018, Pajtler et al. discovered a high expression of <italic>CXorf67</italic> specifically in posterior fossa A (PFA) ependymomas. After that, CXorf67 attracts increasing attention and efforts to explore its potential roles in PFA ependymomas. Based on DNA methylation profiling, ependymomas have been classified into 9 molecular subgroups. Of these 9 subgroups, PFA is one of the most malignant and aggressive ones with the highest incidence. PFA ependymomas mostly happen in infants and young children with a median age of <sc>~3 years old,</sc> and are generally refractory to chemotherapies. Current standard therapy for intracranial ependymomas is surgical resection combined with radiotherapy. However, the lateral localization of PFA ependymomas renders them hard to be removed completely, and together with a lack of chemotherapy options, they generally have a poor prognosis. Research from different labs has so far revealed two independent functions of CXorf67 in PFA ependymomas. One function of CXorf67 is related to the inhibition of PRC2 (Polycomb repressive complex 2) enzymatic activity and thus a global H3K27me3 reduction in PFA ependymomas. Results from several studies consistently suggested that CXorf67 functions as an inhibitor of PRC2 through an H3K27M-like mechanism. These findings implicate CXorf67 as a promising therapeutic target for PFA ependymomas, and efforts to develop drugs based on this PRC2-related function of CXorf67 remain on the way. On the other hand, a recent study revealed the other function of CXorf67 that is involved in DNA damage repair—CXorf67 inhibits DNA homologous recombination repair through blocking PALB2-BRCA2 interaction. This new function of CXorf67 renders it as a biomarker for PARP inhibitor treatment and provides a new treatment option for PFA patients with immediate clinical applicability. In this review, we summarize current findings about the functions and mechanisms of CXorf67, as well as the possible regulatory mechanisms of <italic>CXorf67</italic> expression in PFA ependymomas. We also discussed the clinical implications of the two functions of CXorf67 for PFA ependymomas. In addition to PFA ependymomas, <italic>CXorf67</italic> expression is also observed in diffuse intrinsic pontine gliomas (DIPG) and germ cell tumors. We believe that it will be of great significance to investigate whether <italic>CXorf67</italic> expression could also sensitize these two tumors to PARP inhibitors. Moreover, <italic>CXorf67</italic> is specifically unregulated in PFA, but not in any other ependymoma subgroup; and reasons for this remain currently unclear. Understanding of how <italic>CXorf67 </italic>expression is turned on in PFA ependymomas might enable a controllable expression of <italic>CXorf67</italic> in other types of tumors, thereby opening up new opportunities not only for PFA patients, but possibly also for other cancer patients.