TAp73α drives cancer metastasis via PPI-mediated derepression of the neuronal HDAC2/REST-GABBR2 axis

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-06-10 DOI:10.1016/j.canlet.2025.217867

Nico Murr , Christin Richter , Shailendra K. Gupta , Elke Hammer , Nares Trakooljul , Anja Stoll , Steffen Möller , Lukas E. Neumann , Brigitte M. Pützer , Alf Spitschak

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Abstract

Metastasis is the leading cause of death in patients with malignant melanoma, yet the molecular and transcriptional mechanisms remain elusive. This study reveals a crucial role of the p53 homolog, TAp73α, in promoting melanoma metastasis. Using multi-omics approaches combining transcriptomics, proteomics, cistromics and 3D modeling, we discovered a paradigm-shifting mechanism by which TAp73α binds directly to HDAC2, disassembles the HDAC2/REST repressor complex and aberrantly triggers activation of the neuronal receptor GABBR2 in cancer cells. TAp73α-induced derepression of GABBR2 expression leads to upregulation of EMT markers, promotes cancer cell invasiveness and proliferation, and correlates with poor survival outcomes. Our findings redefine the function of p73 in cancer pathogenesis and identify the TAp73α-HDAC2/REST-GABBR2 axis as a novel driver of melanoma progression. These insights could guide future strategies on melanoma treatment.

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TAp73α通过ppi介导的神经元HDAC2/REST-GABBR2轴的下调来驱动肿瘤转移

转移是恶性黑色素瘤患者死亡的主要原因，但其分子和转录机制仍然难以捉摸。这项研究揭示了p53同源物TAp73α在促进黑色素瘤转移中的重要作用。通过结合转录组学、蛋白质组学、组织学和3D建模的多组学方法，我们发现了一种范式转移机制，通过这种机制，TAp73α直接结合到HDAC2上，破坏HDAC2/REST抑制因子复合物，并异常触发癌细胞中神经元受体GABBR2的激活。tap73 α-诱导的GABBR2表达下调导致EMT标志物上调，促进癌细胞侵袭性和增殖，与不良生存结局相关。我们的研究结果重新定义了p73在癌症发病机制中的功能，并确定了TAp73α-HDAC2/REST-GABBR2轴是黑色素瘤进展的新驱动因素。这些见解可以指导未来的黑色素瘤治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.