The oncogenic axis YAP/MYC/EZH2 impairs PTEN tumor suppression activity enhancing lung tumorigenicity.

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2024-10-25 DOI:10.1038/s41420-024-02216-8

Federica Lo Sardo, Chiara Turco, Beatrice Messina, Andrea Sacconi, Francesca Romana Auciello, Claudio Pulito, Sabrina Strano, Sima Lev, Giovanni Blandino

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引用次数: 0

Abstract

The tumor suppressor PTEN (phosphatase and tensin homolog deleted in chromosome 10) is genetically deleted or downregulated in many cancer types. Loss of PTEN protein expression is frequently found in lung cancer while genetic alterations are less abundant. PTEN expression is regulated at multiple genetic and epigenetic levels and even partial reduction of its expression increases cancer occurrence. We show that YAP and TAZ cooperate with EZH2, and MYC to transcriptionally repress onco-suppressor genes, including PTEN, in non-small cell lung cancer (NSCLC) cells. YAP/TAZ-EZH2-MYC transcriptional regulators form a nuclear complex that represses PTEN transcription, while their combinatorial targeting restores PTEN expression, attenuates NSCLC cell growth, and prevents compensatory responses induced by single treatments. Datasets analysis of NSCLC patients revealed that PTEN expression is negatively correlated to YAP/TAZ, EZH2 and MYC and that low expression of PTEN is predictive of poor prognosis, especially at earlier stages of the disease. These findings highlight the repressive role of the YAP/TAZ-EZH2-MYC axis on tumor-suppressor genes and offer a potential therapeutic strategy for lung cancer patients with low PTEN levels.

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致癌轴YAP/MYC/EZH2损害了PTEN的肿瘤抑制活性，从而增强了肺癌的致病性。

在许多癌症类型中，肿瘤抑制因子 PTEN（10 号染色体上缺失的磷酸酶和天丝蛋白同源物）会发生基因缺失或下调。肺癌中经常发现 PTEN 蛋白表达缺失，而基因改变则较少见。PTEN 的表达在多个遗传和表观遗传水平上受到调控，即使部分减少其表达也会增加癌症的发生率。我们发现，在非小细胞肺癌（NSCLC）细胞中，YAP和TAZ与EZH2和MYC合作转录抑制包括PTEN在内的共抑制基因。YAP/TAZ-EZH2-MYC转录调节因子形成了抑制PTEN转录的核复合物，而它们的组合靶向作用能恢复PTEN的表达，抑制NSCLC细胞的生长，并防止单一疗法引起的代偿反应。对NSCLC患者的数据集分析表明，PTEN的表达与YAP/TAZ、EZH2和MYC呈负相关，PTEN的低表达预示着预后不良，尤其是在疾病的早期阶段。这些发现强调了YAP/TAZ-EZH2-MYC轴对肿瘤抑制基因的抑制作用，并为PTEN水平较低的肺癌患者提供了一种潜在的治疗策略。

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

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.