LAP2α orchestrates alternative lengthening of telomeres suppression through telomeric heterochromatin regulation with HDAC1: unveiling a potential therapeutic target.

Autor: Wang B; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Genetics, School of Basic Medical Science, Institute of Prosthodontics School and Hospital of Stomatology, General Hospital, Tianjin Medical University, 300070, Tianjin, P. R. China.; Department of Hematology, Tianjin First Central Hospital, 300192, Tianjin, P. R. China., Kou H; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Genetics, School of Basic Medical Science, Institute of Prosthodontics School and Hospital of Stomatology, General Hospital, Tianjin Medical University, 300070, Tianjin, P. R. China., Wang Y; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Genetics, School of Basic Medical Science, Institute of Prosthodontics School and Hospital of Stomatology, General Hospital, Tianjin Medical University, 300070, Tianjin, P. R. China., Zhang Q; Department of Clinical Laboratory, First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, P. R. China., Jiang D; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Genetics, School of Basic Medical Science, Institute of Prosthodontics School and Hospital of Stomatology, General Hospital, Tianjin Medical University, 300070, Tianjin, P. R. China., Wang J; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Genetics, School of Basic Medical Science, Institute of Prosthodontics School and Hospital of Stomatology, General Hospital, Tianjin Medical University, 300070, Tianjin, P. R. China., Zhao Z; Department of Pathology, Tianjin Hospital, 300221, Tianjin, P. R. China., Zhou Y; Department of Bioinformatics, The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, P. R. China., Zhang M; Department of Pathology, Jining No.1 People's Hospital, 272000, Jining, Shandong, P. R. China., Sui L; Department of Prosthodontics, School and Hospital of Stomatology, Tianjin Medical University, 300070, Tianjin, P. R. China., Zhao M; Department of Hematology, Tianjin First Central Hospital, 300192, Tianjin, P. R. China., Liu Y; Department of Bone and Soft Tissue Oncology, Tianjin Hospital, 300221, Tianjin, P. R. China. zhking2021@126.com., Liu Y; Department of Radiobiology, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, 300192, Tianjin, P. R. China. liuyang@irm-cams.ac.cn., Shi L; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, P. R. China. shilei@tmu.edu.cn., Wang F; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Genetics, School of Basic Medical Science, Institute of Prosthodontics School and Hospital of Stomatology, General Hospital, Tianjin Medical University, 300070, Tianjin, P. R. China. wangf@tmu.edu.cn.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Oct 19; Vol. 15 (10), pp. 761. Date of Electronic Publication: 2024 Oct 19.
DOI: 10.1038/s41419-024-07116-4
Abstrakt: In response to the challenge of telomere attrition during DNA replication, cancer cells predominantly employ telomerase or, in 10-15% of cases, the alternative lengthening of telomeres (ALT). The intricate details of ALT, however, remain elusive. In this study, we unveil that the knockdown of lamina-associated polypeptide 2 alpha (LAP2α) in ALT cells results in telomere dysfunction, triggering a notable increase in ALT-associated hallmarks, including high frequencies of PML bodies (APBs), C-rich extrachromosomal circles (C-circles), and telomere sister chromatid exchange (T-SCE). Furthermore, LAP2α emerges as a crucial player in break-induced telomere replication for telomerase-positive cells following telomeric double-strand breaks. Mechanistically, our investigation suggests that LAP2α may influence the regulation of the heterochromatic state of telomeres, thereby affecting telomeric accessibility. In line with our findings, LAP2α expression is markedly reduced in ALT-positive osteosarcoma. And the use of methotrexate (MTX) can restore the heterochromatin state altered by LAP2α depletion. This is evidenced by a significant inhibition of tumor proliferation in ALT-positive patient-derived xenograft (PDX) mouse models. These results indicate the important role of LAP2α in regulating ALT activity and offer insights into the interplay between lamina-associated proteins and telomeres in maintaining telomere length. Importantly, our findings may help identify a more appropriate target population for the osteosarcoma therapeutic drug, MTX.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: