<br>CYTOR 促进 FOSL1 相分离和超级增强子的形成，以驱动头颈部鳞状细胞癌中肿瘤出芽细胞的转移,Advanced Science

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CYTOR 促进 FOSL1 相分离和超级增强子的形成，以驱动头颈部鳞状细胞癌中肿瘤出芽细胞的转移
Advanced Science ( IF 14.3 ) Pub Date : 2023-11-30 , DOI: 10.1002/advs.202305002
Wenjin Wang _{1,

2,

3} , Bokai Yun _{1,

2,

3} , Rosalie G Hoyle ₄ , Zhikun Ma ₄ , Shadid Uz Zaman ₄ , Gan Xiong _{1,

2,

3} , Chen Yi _{1,

2,

3} , Nan Xie _{1,

2,

3} , Ming Zhang _{1,

2,

3} , Xiqiang Liu ₅ , Dipankar Bandyopadhyay _{6,

7} , Jiong Li _{4,

7,

8,

9} , Cheng Wang _{1,

2,

3}

Affiliation

肿瘤出芽（TB）是一个小的肿瘤细胞簇，具有高度侵袭性的行为，位于侵袭性肿瘤前沿之前。然而，结核病的分子和生物学特征以及控制结核病表型的调节机制仍不清楚。这项研究表明，结核病表现出特殊的动态基因特征，具有干性和部分上皮-间充质转化（p-EMT）。重要的是，CYTOR 的核表达被确定为控制 TB 细胞干性和 p-EMT 表型的关键调节因子，靶向 CYTOR 显着抑制头颈部鳞状细胞癌（HNSCC）的 TB 形成、肿瘤生长和淋巴结转移。从机制上讲，CYTOR 通过促进 FOSL1 相分离缩合物的形成来建立 FOSL1 依赖性超级增强子（SE），从而促进 TB 细胞的致瘤性和转移。CYTOR 的耗竭导致 FOSL1 依赖性 SE 的破坏，从而导致癌症干性和促转移基因失活。反过来，FOSL1 的激活会促进 CYTOR 的转录。这些发现表明，CYTOR 是一种超级 lncRNA，通过促进 FOSL1 相分离和 SEs 的形成来控制结核细胞的干性和转移，这可能是 HNSCC 治疗干预的一个有吸引力的靶点。

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CYTOR Facilitates Formation of FOSL1 Phase Separation and Super Enhancers to Drive Metastasis of Tumor Budding Cells in Head and Neck Squamous Cell Carcinoma

Tumor budding (TB) is a small tumor cell cluster with highly aggressive behavior located ahead of the invasive tumor front. However, the molecular and biological characteristics of TB and the regulatory mechanisms governing TB phenotypes remain unclear. This study reveals that TB exhibits a particular dynamic gene signature with stemness and partial epithelial-mesenchymal transition (p-EMT). Importantly, nuclear expression of CYTOR is identified to be the key regulator governing stemness and the p-EMT phenotype of TB cells, and targeting CYTOR significantly inhibits TB formation, tumor growth and lymph node metastasis in head and neck squamous cell carcinoma (HNSCC). Mechanistically, CYTOR promotes tumorigenicity and metastasis of TB cells by facilitating the formation of FOSL1 phase-separated condensates to establish FOSL1-dependent super enhancers (SEs). Depletion of CYTOR leads to the disruption of FOSL1-dependent SEs, which results in the inactivation of cancer stemness and pro-metastatic genes. In turn, activation of FOSL1 promotes the transcription of CYTOR. These findings indicate that CYTOR is a super-lncRNA that controls the stemness and metastasis of TB cells through facilitating the formation of FOSL1 phase separation and SEs, which may be an attractive target for therapeutic interventions in HNSCC.

更新日期：2023-11-30

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