LAP2α Orchestrates Alternative Lengthening of Telomeres Suppression through Telomeric Heterochromatin Regulation with HDAC1: Unveiling a Potential Therapeutic Target

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 the process of break-induced telomere replication for telomerase-positive cells following telomeric double-strand breaks. Mechanistically, our investigation underscores LAP2α's role in hindering the recruitment of homologous recombination factors (e.g., RAD52 and RPA2) to telomeres. This occurs through the regulation of the heterochromatic state of telomeres, thereby increasing telomeric accessibility. Consistent with our findings, LAP2α expression is markedly diminished in ALT-positive Osteosarcoma. The use of methotrexate (MTX), which restores the lost heterochromatin state induced by LAP2α depletion, effectively reverses ALT characteristics. This is highlighted by a significant inhibition of tumor proliferation, specifically in ALT-positive patient-derived xenograft (PDX) mouse models. These results underscore the critical role of LAP2α in regulating ALT activity, offering significant insights into the interplay between lamina-associated proteins and telomeres for maintaining telomere length. Of paramount significance, our findings contribute to the identification of a more appropriate target population for the osteosarcoma therapeutic drug, MTX.