Khan Bushra, Lanzuolo Chiara, Rosti Valentina, Santarelli Philina, Pich Andreas, Kraft Theresia, Amrute-Nayak Mamta, Nayak Arnab
Institute of Molecular and Cell Physiology, Hannover Medical School, Hannover, Germany.
Istituto Nazionale Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy.
iScience. 2024 Sep 10;27(10):110913. doi: 10.1016/j.isci.2024.110913. eCollection 2024 Oct 18.
Chemotherapeutics used in cancer therapy are often linked to muscle wasting or cachexia. Insights into the molecular basis of chemotherapy-induced cachexia is essential to improve treatment strategies. Here, we demonstrated that Sorafenib-tyrosine kinase inhibitor (TKI) class of chemotherapeutic agents-induced cachexia. System-wide analyses revealed that Sorafenib alters the global transcriptional program and proteostasis in muscle cells. Mechanistically, Sorafenib treatment reduced active epigenetic mark H3K4 methylation on distinct muscle-specific genes by impeding chromatin association of SET1A-catalytic component of the SET1/MLL histone methyltransferase complex. This mechanism favored transcriptional disorientation that led to disrupted sarcomere assembly, calcium homeostasis and mitochondrial respiration. Consequently, the contractile ability of muscle cells was severely compromised. Interestingly, the other prominent TKIs Nilotinib and Imatinib did not exert similar effects on muscle cell physiology. Collectively, we identified an unanticipated transcriptional mechanism underlying Sorafenib-induced cachexia. Our findings hold the potential to strategize therapy regimens to minimize chemotherapy-induced cachexia.
用于癌症治疗的化疗药物常常与肌肉萎缩或恶病质相关。深入了解化疗诱导恶病质的分子基础对于改进治疗策略至关重要。在此，我们证明了索拉非尼——一类化疗药物酪氨酸激酶抑制剂（TKI）——可诱导恶病质。全系统分析表明，索拉非尼改变了肌肉细胞中的整体转录程序和蛋白质稳态。从机制上讲，索拉非尼治疗通过阻碍SET1/MLL组蛋白甲基转移酶复合物的SET1A催化成分与染色质的结合，降低了不同肌肉特异性基因上的活性表观遗传标记H3K4甲基化。这种机制有利于转录紊乱，导致肌节组装、钙稳态和线粒体呼吸受到破坏。因此，肌肉细胞的收缩能力严重受损。有趣的是，其他著名的TKI药物尼罗替尼和伊马替尼对肌肉细胞生理学没有产生类似影响。总体而言，我们确定了索拉非尼诱导恶病质背后一种意想不到的转录机制。我们的研究结果有可能制定治疗方案，以尽量减少化疗诱导的恶病质。
