Background: Due to the limitations of strategies for its early diagnosis and treatment, pancreatic cancer (PC) remains a substantial human health threat. We previously discovered a methylation-mediated lncRNA, LINC00261, which is downregulated in PC tissues. However, the underlying role of LINC00261 in PC remains largely unknown./nMethods: Quantitative real-time PCR and in situ hybridization were performed to evaluate the expression levels of LINC00261 in PC, adjacent nontumor and normal pancreas tissues. The clinical significance of LINC00261 was assessed in multicenter PC samples. The functions of LINC00261 in PC were investigated by gain- and loss-of-function assays in vitro and in vivo. Potential downstream pathways and mechanisms were explored via RNA sequencing and bioinformatic analyses. RNA immunoprecipitation and chromatin immunoprecipitation assays were used to validate the underlying mechanisms. Pyrosequencing and targeted demethylation of the LINC00261 promoter were performed to explore the upstream epigenetic mechanisms and therapeutic potential./nResults: LINC00261 was significantly downregulated in PC tissues, and its expression was positively associated with the prognosis of PC patients. Phenotypic studies indicated that LINC00261 overexpression significantly suppressed PC cell proliferation, migration and metastasis in vitro and in vivo. c-Myc was identified as a downstream target of LINC00261. LINC00261 repressed c-Myc transcription by physically interacting and binding with the bromo domain of p300/CBP, preventing the recruitment of p300/CBP to the promoter region of c-Myc and decreasing the H3K27Ac level. Moreover, the methylation level of the LINC00261 promoter was high in PC tissues and was correlated with poor prognosis. Targeted demethylation of the LINC00261 promoter inhibited PC progression both in vitro and in vivo./nConclusions: Our findings indicate that methylation-mediated LINC00261 suppresses PC progression by epigenetically repressing c-Myc expression. These findings expand the therapeutic potential of LINC00261, possibly providing evidence to support the development of epigenetic drugs or therapeutic strategies. This research adds further insights into the etiology of PC and indicates that LINC00261 may be a prognostic and therapeutic target in PC.

中文翻译：

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甲基化介导的 LINC00261 通过表观遗传抑制 c-Myc 转录来抑制胰腺癌的进展。


背景：由于早期诊断和治疗策略的局限性，胰腺癌（PC）仍然对人类健康构成重大威胁。我们之前发现了一种甲基化介导的 lncRNA，LINC00261，它在 PC 组织中下调。然而，LINC00261 在 PC 中的潜在作用仍然很大程度上未知。/n方法：进行定量实时 PCR 和原位杂交来评估 LINC00261 在 PC、邻近非肿瘤和正常胰腺组织中的表达水平。 LINC00261 的临床意义在多中心 PC 样本中进行了评估。通过体外和体内功能获得和丧失测定来研究 LINC00261 在 PC 中的功能。通过 RNA 测序和生物信息学分析探索了潜在的下游途径和机制。 RNA 免疫沉淀和染色质免疫沉淀测定用于验证潜在机制。对LINC00261启动子进行焦磷酸测序和靶向去甲基化，探讨其上游表观遗传机制和治疗潜力。/n结果： LINC00261在PC组织中显着下调，其表达与PC患者的预后呈正相关。表型研究表明，LINC00261 过表达可显着抑制体外和体内PC 细胞的增殖、迁移和转移。 c-Myc 被确定为 LINC00261 的下游靶标。 LINC00261 通过与 p300/CBP 的溴结构域物理相互作用和结合来抑制 c-Myc 转录，阻止 p300/CBP 募集到 c-Myc 启动子区域并降低 H3K27Ac 水平。 此外，PC 组织中 LINC00261 启动子的甲基化水平较高，与不良预后相关。 LINC00261 启动子的靶向去甲基化在体外和体内均抑制 PC 进展。/n结论：我们的研究结果表明，甲基化介导的 LINC00261 通过表观遗传抑制 c-Myc 表达来抑制 PC 进展。这些发现扩大了 LINC00261 的治疗潜力，可能为支持表观遗传药物或治疗策略的开发提供证据。这项研究进一步深入了解了 PC 的病因，并表明 LINC00261 可能是 PC 的预后和治疗靶点。