<br>FTO 通过 m6A-YTHDF2 依赖性方式转录后激活 HSF1 促进多发性骨髓瘤进展,Molecular Therapy

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FTO 通过 m6A-YTHDF2 依赖性方式转录后激活 HSF1 促进多发性骨髓瘤进展
Molecular Therapy ( IF 12.1 ) Pub Date : 2021-12-13 , DOI: 10.1016/j.ymthe.2021.12.012
Aoshuang Xu ₁ , Jiasi Zhang ₁ , Liping Zuo ₁ , Han Yan ₁ , Lei Chen ₁ , Fei Zhao ₁ , Fengjuan Fan ₁ , Jian Xu ₁ , Bo Zhang ₁ , Yuyang Zhang ₁ , Xuejiao Yin ₁ , Qianwen Cheng ₁ , Su Gao ₁ , Jun Deng ₁ , Heng Mei ₁ , Zhiping Huang ₂ , Chunyan Sun ₁ , Yu Hu ₁

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N-甲基腺苷（mA）作为真核mRNA最普遍的内部修饰，在多种癌症中发挥着至关重要的作用，但其在多发性骨髓瘤（MM）发病机制中的作用尚未得到研究。在这项研究中，我们发现 MM 患者浆细胞 (PC) 中的 m6A 甲基化显着降低，并表明异常的 m6A 水平主要是由于去甲基酶脂肪量和肥胖相关蛋白 (FTO) 的上调所致。功能获得和功能丧失研究表明，FTO 在 MM 中发挥促进肿瘤和促转移的作用。结合 m6A 和 RNA 测序 (RNA-seq) 以及随后的验证和功能研究确定热休克因子 1 (HSF1) 是 FTO 介导的 m6A 修饰的功能靶点。 FTO 以 YTHDF2 依赖性方式靶向 HSF1/HSP，显着促进 MM 细胞增殖、迁移和侵袭。 FTO 抑制，特别是与硼替佐米 (BTZ) 治疗联合使用时，可协同抑制 NOD-Prkdcil2rg/Nju (NCG) 小鼠中的骨髓瘤骨肿瘤形成和髓外扩散。我们证明了 m6A 去甲基酶 FTO 在 MM 进展中的功能重要性，特别是在促进髓外骨髓瘤 (EMM) 形成方面，并提出 FTO-HSF1/HSP 轴作为 MM 潜在的新型治疗靶点。

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FTO promotes multiple myeloma progression by posttranscriptional activation of HSF1 in an m6A-YTHDF2-dependent manner

N-methyladenosine (mA), as the most pervasive internal modification of eukaryotic mRNA, plays a crucial role in various cancers, but its role in multiple myeloma (MM) pathogenesis has not yet been investigated. In this study, we revealed significantly decreased mA methylation in plasma cells (PCs) from MM patients and showed that the abnormal mA level resulted mainly from upregulation of the demethylase fat mass and obesity-associated protein (FTO). Gain- and loss-of-function studies demonstrated that FTO plays a tumor-promoting and pro-metastatic role in MM. Combined mA and RNA sequencing (RNA-seq) and subsequent validation and functional studies identified heat shock factor 1 (HSF1) as a functional target of FTO-mediated mA modification. FTO significantly promotes MM cell proliferation, migration, and invasion by targeting HSF1/HSPs in a YTHDF2-dependent manner. FTO inhibition, especially when combined with bortezomib (BTZ) treatment, synergistically inhibited myeloma bone tumor formation and extramedullary spread in NOD-Prkdcil2rg/Nju (NCG) mice. We demonstrated the functional importance of mA demethylase FTO in MM progression, especially in promoting extramedullary myeloma (EMM) formation, and proposed the FTO-HSF1/HSP axis as a potential novel therapeutic target in MM.

更新日期：2021-12-13

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