LAP2α通过端粒异染色质调控HDAC1协调端粒抑制的替代性延长:揭示潜在的治疗靶点。

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Bing Wang, Haomeng Kou, Yuwen Wang, Qi Zhang, Duo Jiang, Juan Wang, Ziqin Zhao, Yao Zhou, Miaomiao Zhang, Lei Sui, Mingfeng Zhao, Yancheng Liu, Yang Liu, Lei Shi, Feng Wang
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引用次数: 0

摘要

为了应对DNA复制过程中端粒损耗的挑战,癌细胞主要利用端粒酶,或在10-15%的情况下利用端粒替代性延长(ALT)。然而,ALT的复杂细节仍然难以捉摸。在这项研究中,我们发现在ALT细胞中敲除片层相关多肽2α(LAP2α)会导致端粒功能障碍,引发ALT相关标志物的显著增加,包括高频率的PML体(APB)、富含C的染色体外圈(C圈)和端粒姐妹染色单体交换(T-SCE)。此外,LAP2α还是端粒双链断裂后端粒酶阳性细胞断裂诱导端粒复制的关键参与者。从机理上讲,我们的研究表明,LAP2α可能会影响端粒异染色质状态的调节,从而影响端粒的可及性。与我们的研究结果一致,LAP2α在ALT阳性骨肉瘤中的表达明显减少。而使用甲氨蝶呤(MTX)可以恢复因LAP2α消耗而改变的异染色质状态。在 ALT 阳性的患者异种移植(PDX)小鼠模型中,肿瘤的增殖受到了明显的抑制,就证明了这一点。这些结果表明了LAP2α在调节ALT活性中的重要作用,并为了解片层相关蛋白和端粒在维持端粒长度中的相互作用提供了见解。重要的是,我们的发现可能有助于为骨肉瘤治疗药物MTX确定更合适的目标人群。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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 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.

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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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