Elevated CXorf67 Expression in PFA Ependymomas Suppresses DNA Repair and Sensitizes to PARP Inhibitors

Jichang Han; Meng Yu; Yiqin Bai; Jianzhong Yu; Fei Jin; Chen Li; Rong Zeng; Jinghong Peng; Ao Li; Xiaomin Song; Hao Li; Dianqing Wu; Lin Li

doi:10.1016/j.ccell.2020.10.009

Elevated CXorf67 Expression in PFA Ependymomas Suppresses DNA Repair and Sensitizes to PARP Inhibitors

Cancer Cell. 2020 Dec 14;38(6):844-856.e7. doi: 10.1016/j.ccell.2020.10.009. Epub 2020 Nov 12.

Authors

Jichang Han¹, Meng Yu¹, Yiqin Bai², Jianzhong Yu³, Fei Jin², Chen Li⁴, Rong Zeng⁵, Jinghong Peng², Ao Li⁶, Xiaomin Song², Hao Li⁷, Dianqing Wu⁸, Lin Li⁹

Affiliations

¹ State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
² State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
³ Department of Neurosurgery, Children's Hospital of Fudan University, Shanghai 201102, China.
⁴ CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
⁵ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
⁶ Department of Pharmacology, Yale School of Medicine, New Haven, CT 208089, USA.
⁷ Department of Neurosurgery, Children's Hospital of Fudan University, Shanghai 201102, China. Electronic address: [email protected].
⁸ Department of Pharmacology, Yale School of Medicine, New Haven, CT 208089, USA. Electronic address: [email protected].
⁹ State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: [email protected].

Abstract

Ependymoma is the third most common pediatric tumor with posterior fossa group A (PFA) being its most aggressive subtype. Ependymomas are generally refractory to chemotherapies and thus lack any effective treatment. Here, we report that elevated expression of CXorf67 (chromosome X open reading frame 67), which frequently occurs in PFA ependymomas, suppresses homologous recombination (HR)-mediated DNA repair. Mechanistically, CXorf67 interacts with PALB2 and inhibits PALB2-BRCA2 interaction, thereby inhibiting HR repair. Concordantly, tumor cells with high CXorf67 expression levels show increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with radiotherapy. Thus, our findings have revealed a role of CXorf67 in HR repair and suggest that combination of PARP inhibitors with radiotherapy could be an effective treatment option for PFA ependymomas.

Keywords: CXorf67; PALB2; PARP inhibitors; ependymoma tumor; homologous recombination repair; radiotherapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
BRCA2 Protein / metabolism*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Proliferation / radiation effects
Cell Survival / drug effects
Cell Survival / radiation effects
Chemoradiotherapy
Ependymoma / genetics
Ependymoma / metabolism
Ependymoma / therapy*
Fanconi Anemia Complementation Group N Protein / metabolism*
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects
Gene Expression Regulation, Neoplastic / radiation effects
Humans
Infratentorial Neoplasms / genetics
Infratentorial Neoplasms / metabolism
Infratentorial Neoplasms / therapy*
Mice
Oligonucleotide Array Sequence Analysis
Oncogene Proteins / genetics
Oncogene Proteins / metabolism*
Poly(ADP-ribose) Polymerase Inhibitors / administration & dosage*
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
Recombinational DNA Repair / drug effects
Recombinational DNA Repair / radiation effects
Up-Regulation
Xenograft Model Antitumor Assays

Substances

BRCA2 Protein
BRCA2 protein, human
EZHIP protein, human
Fanconi Anemia Complementation Group N Protein
Oncogene Proteins
PALB2 protein, human
Poly(ADP-ribose) Polymerase Inhibitors

Grants and funding

R01 CA214703/CA/NCI NIH HHS/United States