Interaction between p53 and Ras signaling controls cisplatin resistance via HDAC4-and HIF-1α-mediated regulation of apoptosis and autophagy
Interaction between p53 and Ras signaling controls cisplatin resistance via HDAC4-and HIF-1α-mediated regulation of apoptosis and autophagy
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p53 和 Ras 信号传导之间的相互作用通过 HDAC4 和 HIF-1 α 介导的细胞凋亡和自噬调节来控制顺铂耐药
DOI：
10.7150/thno.29673
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Yang, Gong
中科院分区：
文献类型：
--
作者：
Zhang, Xiaofei;Qi, Zihao;Yang, Gong
p53和RAS信号之间的相互作用调节癌症化疗耐药性，但详细机制尚不清楚。本研究旨在探讨p53和RAS在卵巢癌顺铂耐药中的相互作用，以探索潜在的治疗靶点。方法：将MAPK/ERK（S35和E38）或PI 3 K/AKT（C40）或两者均具有活性的p53和RAS突变体依次导入p53缺失的卵巢癌细胞系SKOV 3中。使用Gene Chip Prime View Human Gene Expression arrays（Affytechnology）进行比较微阵列分析。使用建立的细胞系通过p53诱导和/或顺铂处理进行自噬和凋亡的体外测定和体内动物实验。评估了来自TCGA的523例浆液性卵巢癌病例中HDAC 4和HIF-1 α或CREBZF之间的相关性以及HDAC 4、HIF-1 α、CREBZF、ERK、AKT和p53 mRNA水平与患者生存率的相关性。我们发现，p53和RAS突变体通过Bax、Bcl 2、ATG 3的失调，ATG12 ERK和AKT活性RAS突变体相互抑制以赋予或剥夺顺铂抗性。进一步的研究表明，p53诱导HIF-1 α降解和HDAC 4胞质易位和磷酸化。S35、E38和V12促进HDAC 4磷酸化及其与HIF-1 α一起沿着胞质易位，而C40不促进。RAS突变细胞中野生型p53表达增强卵巢癌和肺癌细胞中HIF-1 α的周转自噬和抗凋亡过程可以通过HDAC 4和HIF 1-α的过表达和细胞质易位来促进。此外，HDAC 4的磷酸化和胞质易位激活转录因子CREBZF以促进ATG 3的转录。HDAC 4或CREBZF高表达预测卵巢癌患者的总生存期（OS）和/或无进展生存期（PFS）较差，而HIF-1 α高表达与OS较差或良好在统计学上相关，这取决于p53状态。HIF-1 α和HDAC 4可能介导p53和RAS信号之间的相互作用，通过细胞凋亡的失调积极控制卵巢癌顺铂耐药，自噬靶向HDAC 4、HIF-1 α和CREBZF可考虑用于治疗p53和RAS突变的卵巢癌。
The interplay between p53 and RAS signaling regulates cancer chemoresistance, but the detailed mechanism is unclear. In this study, we investigated the interactive effects of p53 and RAS on ovarian cancer cisplatin resistance to explore the potential therapeutic targets.Methods: An inducible p53 and RAS mutants active in either MAPK/ERK (S35 and E38) or PI3K/AKT (C40) or both (V12) were sequentially introduced into a p53-null ovarian cancer cell line-SKOV3. Comparative microarray analysis was performed using Gene Chip Prime View Human Gene Expression arrays (Affymetrix). In vitro assays of autophagy and apoptosis and in vivo animal experiments were performed by p53 induction and/or cisplatin treatment using the established cell lines. The correlation between HDAC4 and HIF-1 alpha or CREBZF and the association of HDAC4, HIF-1 alpha, CREBZF, ERK, AKT, and p53 mRNA levels with patient survival in 523 serous ovarian cancer cases from TCGA was assessed.Results: We show that p53 and RAS mutants differentially control cellular apoptosis and autophagy to inhibit or to promote chemoresistance through dysregulation of Bax, Bcl2, ATG3, and ATG12. ERK and AKT active RAS mutants are mutually suppressive to confer or to deprive cisplatin resistance. Further studies demonstrate that p53 induces HIF-1 alpha degradation and HDAC4 cytoplasmic translocation and phosphorylation. S35, E38, and V12 but not C40 promote HDAC4 phosphorylation and its cytoplasmic translocation along with HIF-1 alpha. Wild-type p53 expression in RAS mutant cells enhances HIF-1 alpha turnover in ovarian and lung cancer cells. Autophagy and anti-apoptotic processes can be promoted by the overexpression and cytoplasmic translocation of HDAC4 and HIF1-alpha. Moreover, the phosphorylation and cytoplasmic translocation of HDAC4 activate the transcription factor CREBZF to promote ATG3 transcription. High HDAC4 or CREBZF expression predicted poor overall survival (OS) and/or progression-free survival (PFS) in ovarian cancer patients, whereas high HIF-1 alpha expression was statistically correlated with poor or good OS depending on p53 status.Conclusion: HIF-1 alpha and HDAC4 may mediate the interaction between p53 and RAS signaling to actively control ovarian cancer cisplatin resistance through dysregulation of apoptosis and autophagy. Targeting HDAC4, HIF-1 alpha and CREBZF may be considered in treatment of ovarian cancer with p53 and RAS mutations.