HMGB1/SET/HAT1 complex-mediated SASH1 repression drives glycolysis and metastasis in lung adenocarcinoma
HMGB1/SET/HAT1 complex-mediated SASH1 repression drives glycolysis and metastasis in lung adenocarcinoma
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DOI：
10.1038/s41388-023-02850-z
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发表时间：
2023-10-04
期刊：
影响因子：
8
通讯作者：
Yang，Lili
中科院分区：
文献类型：
--
作者：
Kou，Fan;Wu，Lei;Yang，Lili
高迁移率族盒 1 (HMGB1) 可以增强核结合位点与核小体和转录因子的稳定性和可及性。最近，HMGB1被认为是肿瘤谷氨酰胺的正调节因子，其过度表达与肿瘤发生和癌症进展相关。然而，HMGB1 在肺腺癌 (LUAD) 癌症进展过程中调节糖酵解的功能和机制仍不清楚。在这里，我们发现 LUAD 样本中细胞内 HMGB1 持续上调，并且与肿瘤分级和较差的生存率呈正相关。 HMGB1通过与SET和HAT1的物理相互作用促进糖酵解并促进转移，形成HMGB1/SET/HAT1复合物，抑制LUAD中H3K9和H3K27乙酰化。功能蛋白复合物协调组蛋白修饰来抑制SASH1的表达，从而进一步促进糖酵解并诱导体内外转移。与此相一致的是，在人类LUAD标本中，SASH1的表达与HMGB1、SET和GLUT1呈负相关，与HAT1呈正相关。临床上，HMGB1高表达和SASH1低表达的LUAD患者临床结果最差。总的来说，这项研究的结果揭示了 HMGB1 通过与 SET 和 HAT1 物理相互作用减弱 H3K9ace 和 H3K27ace 在糖酵解和转移中的关键作用，这可能有助于未来的靶向治疗。
High-mobility group box 1 (HMGB1) can enhance the stability and accessibility of nucleus binding sites to nucleosomes and transcription factors. Recently, HMGB1 has been recognized as a positive regulator of tumor glutamine, and its overexpression has been correlated with tumorigenesis and cancer progression. However, functions and mechanisms of HMGB1 in regulation of glycolysis during cancer progression in lung adenocarcinoma (LUAD) is still unclear. Here, we found that intracellular HMGB1 was consistently upregulated in LUAD specimens, and positively relevant to tumor grade and poor survival. HMGB1 facilitated glycolysis and promoted metastasis through physical interaction with SET and HAT1, forming HMGB1/SET/HAT1 complex that inhibited H3K9 and H3K27 acetylation in LUAD. The functional proteins complex coordinated histone modification to suppress the expression of SASH1, thus further facilitating glycolysis and inducing the metastasis in vitro and in vivo. Consistent with this, the expression of SASH1 was negatively correlated with HMGB1, SET and GLUT1, and positively correlated with HAT1 in human LUAD specimens. Clinically, LUAD patients with high expression of HMGB1 and low expression of SASH1 exhibited the worst clinical outcomes. Overall, the findings of this study revealed the critical role of HMGB1 in glycolysis and metastasis by attenuating H3K9ace and H3K27ace through physical interacted with SET and HAT1, which may facilitate future targeted therapies.