The developmental regulator HAND1 inhibits gastric carcinogenesis through enhancing ER stress apoptosis via targeting CHOP and BAK which is augmented by cisplatin.
The developmental regulator HAND1 inhibits gastric carcinogenesis through enhancing ER stress apoptosis via targeting CHOP and BAK which is augmented by cisplatin.
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DOI：
10.7150/ijbs.76345
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发表时间：
2023
影响因子：
9.2
通讯作者：
Hu X
中科院分区：
文献类型：
--
作者：
Kuang Y;He Z;Li L;Wang C;Cheng X;Shi Q;Fu G;Ying J;Tao Q;Hu X
抑癌基因的表观遗传干扰，特别是异常的CpG甲基化，在胃癌的发病机制中起着至关重要的作用。通过CpG甲基组和表达谱分析，发现发育转录因子HAND1在GC中发生甲基化并下调表达。然而，它在GC进展中的作用和潜在机制还知之甚少。在这里，我们发现HAND1在GC中经常被启动子甲基化下调，并且与GC患者的肿瘤进展和不良预后显著相关。HAND1在胃癌患者中的高表达与显著较高的5年总生存率相关。HAND1的异位表达抑制了体内外GC细胞的生长和迁移。HAND1的表达增加了细胞内ROS水平和细胞内钙离子浓度，通过内质网应激/线粒体介导的细胞凋亡增强了顺铂诱导的细胞凋亡。CHOP和BAK基因敲除可减弱HAND1诱导的细胞凋亡。CHOP过表达可增加BAK的表达。HAND1与CHOP相互作用，也直接与CHOP和BAK启动子结合，正向调节BAK转录。因此，本研究证明HAND1是一种肿瘤抑制基因，在GC中甲基化，通过CHOP和BAK诱导ER应激和细胞凋亡，顺铂可增强该基因的表达。HAND1低表达是胃癌预后不良的独立因素。HAND1启动子的肿瘤特异性甲基化可作为胃癌的候选生物标志物。
Epigenetic disruption of tumor suppressor genes, particularly aberrant CpG methylation, plays a crucial role in gastric cancer (GC) pathogenesis. Through CpG methylome and expression profiling, a developmental transcription factor - Hand-And-Neural-crest-Derivative-expressed 1 (HAND1), was identified methylated and downregulated in GC. However, its role and underlying mechanisms in GC progression are poorly understood. Here, we show that HAND1 was frequently downregulated in GC by promoter methylation, and significantly correlated with tumor progression and poor prognosis of GC patients. High expression of HAND1 in GC patients was associated with significantly higher 5-year overall survival rates. Ectopic expression of HAND1 inhibited GC cell growth and migration in vitro and in vivo. HAND1 expression increased ROS levels and cytosolic Ca2+ concentration, enhanced cisplatin-induced apoptosis through endoplasmic reticulum (ER) stress/mitochondria-mediated apoptosis. Knockdown of CHOP and BAK attenuated HAND1-induced cell apoptosis. Overexpression of CHOP increased BAK expression. HAND1 interacts with CHOP, also directly binds to CHOP and BAK promoters and positively regulates BAK transcription. Thus, the present study demonstrates that HAND1 is a tumor suppressor gene methylated in GC, induces ER stress and apoptosis via CHOP and BAK, which is augmented by cisplatin. Low HAND1 expression is an independent poor prognostic factor for GC. The tumor-specific methylation of HAND1 promoter could be a candidate biomarker for GC.
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