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浙江大学学报（医学版）
浙江大学学报（医学版）  2022, Vol. 51 Issue (5): 647-655    DOI: 10.3724/zdxbyxb-2022-0459
综述     
恶性肿瘤新靶标PHF5A的研究现状及治疗展望
李曼1,程倩倩1,王效静2,3,杨燕1,*()
1. 蚌埠医学院第一附属医院肿瘤内科，安徽 蚌埠 233004
2. 呼吸系病临床基础安徽省重点实验室，安徽 蚌埠 233004
3. 蚌埠医学院第一附属医院分子诊断中心，呼吸与危重症医学科，安徽 蚌埠 233004
Research progress and therapeutic prospect of PHF5A acting as a new target for malignant tumors
LI Man1,CHENG Qianqian1,WANG Xiaojing2,3,YANG Yan1,*()
1. Department of Medical Oncology, the First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, Anhui Province, China;
2. Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, Bengbu 233004, Anhui Province, China;
3. Molecular Diagnosis Center, Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, Anhui Province, China
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摘要：

植物同源域锌指蛋白5A（PHF5A）是PHD-finger样蛋白超家族成员之一，广泛表达于真核生物细胞核中，其PHD-finger样结构域是蛋白质-DNA或蛋白质-蛋白质相互作用区。PHF5A除作为剪接体蛋白组成亚单位调控靶基因的选择性剪接外，还在胚胎干细胞的多潜能性维持、染色质结构重塑、DNA损伤修复、胚胎形成与组织形态发育等方面发挥重要作用。近年来，越来越多的研究集中在探索PHF5A的剪接体相关功能和非剪接体相关功能，及其功能异常与乳腺癌、肺癌、结直肠癌等多种恶性肿瘤的发生、发展及预后的关系，并发现其潜在机制可能包括介导靶基因的异常选择性剪接、作为原癌基因/蛋白激活下游信号通路、作为核转录因子或辅因子调控异常的基因转录等。此外，PHF5A还参与某些肿瘤干细胞的生长调控。本文就PHF5A的结构及功能特点及其在多种恶性肿瘤发生发展中的作用进行综述，以期为抗肿瘤治疗提供潜在作用靶点。
关键词： 植物同源域锌指蛋白5A;  恶性肿瘤;  胚胎干细胞;  肿瘤干细胞;  选择性剪接;  综述    
Abstract:

PHD-finger domain protein 5A (PHF5A) is a member of the PHD-finger like protein superfamily and widely expressed in the nucleus of eukaryotes. The PHD-finger like domain is a protein-DNA or protein-protein interaction region. In addition to regulate alternative splicing of target genes as a spliceosome protein subunit, PHF5A is also involved in pluripotency maintenance of embryonic stem cells, chromatin remodeling, DNA damage repair, embryogenesis and histomorphological development. Recently, increasing studies have focused on exploring spliceosome-related and non-spliceosome-related functions of PHF5A and its relationship with the tumorigenesis, development and patient prognosis of various malignant tumors, such as breast cancer, lung cancer and colorectal cancer. The underlying mechanisms of PHF5A may include mediating aberrant alternative splicing of target genes, activating downstream signaling pathways as an oncogene/protein, and regulating abnormal gene transcription as a nuclear transcription factor or cofactor. Besides, PHF5A was also found to be involved in the growth regulation of cancer stem cells. In this review, we aimed to delineate the structural and functional characteristics of PHF5A, to summarize its role in the occurrence and development of malignant tumors hitherto described, and to provide potential targets for anti-tumor therapy.
Key words: PHD-finger domain protein 5A    Malignant tumor    Embryonic stem cell    Cancer stem cell    Alternative splicing    Review
收稿日期: 2022-08-03 出版日期: 2022-12-28
CLC:  R73  
基金资助: 国家自然科学基金（82072585）; 安徽省自然科学基金（2008085MH238）; 安徽省高校优秀青年人才支持计划（gxyq2022042）; 蚌埠医学院研究生科研创新计划（Byycx20046）
通讯作者: 杨燕     E-mail: an
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引用本文:

李曼,程倩倩,王效静,杨燕. 恶性肿瘤新靶标PHF5A的研究现状及治疗展望[J]. 浙江大学学报（医学版）, 2022, 51(5): 647-655.

LI Man,CHENG Qianqian,WANG Xiaojing,YANG Yan. Research progress and therapeutic prospect of PHF5A acting as a new target for malignant tumors. J Zhejiang Univ (Med Sci), 2022, 51(5): 647-655.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2022-0459    或    https://www.zjujournals.com/med/CN/Y2022/V51/I5/647

图1  剪接复合物U2-snRNP组成结构示意图 U2-snRNP主要由SF3A、SF3B1/2/3、PHF5A等构成, 在识别及去除前mRNA内含子中发挥重要作用. U2-snRNP：U2-核小核糖核蛋白；PHF5A：植物同源域锌指蛋白5A；SF：剪接因子；U2AF：U2小核核糖核蛋白辅助因子.

肿瘤类型

功 能

靶基因/蛋白

相关机制或通路

作 用

参考文献

乳腺癌

剪接因子

FASTK

作为表观遗传的细胞凋亡抑制因子调控FASTK-AS轴

增强细胞增殖、迁移能力和致瘤性, 抑制细胞凋亡

[3]

非小细胞肺癌及其肿瘤干细胞

癌基因；剪接因子

IGFBP3、DDIT3、CHD4和HDAC8、PIK3CB、SKP2d等

PHF5A-TOMM22-氧化磷酸化调控网络；CHD4-PHF5A相互作用激活RhoA/ROCK通路

增强细胞增殖、迁移、侵袭能力和致瘤性, 抑制细胞凋亡, 促进异种移植瘤生长；与肿瘤进展及患者预后不良相关

[ 4, 17, 30- 32 ]

结直肠癌

剪接因子

KDM3A、TEAD2

增强U2-snRNP亚单位间的相互作用, 影响前mRNA的整体剪接模式；高PHF5A-K29乙酰化诱导的AS上调KDM3A并激活Wnt通路, 进而调控细胞应激反应；促进TEAD2外显子2包含体剪接以激活Yes相关蛋白

在体内外促进细胞增殖、转移；促进异种移植瘤生长；与患者较差的临床分期及较低的3年存活率密切相关

[ 5, 18 ]

肝细胞癌

癌基因

NF-κB

增强NF-κB通路活性，上调MMP9及Slug

促进肝细胞癌迁移、侵袭及肿瘤进展

[25]

胃癌

癌基因

NF-κB

增强NF-κB通路活性，上调磷酸化IκBα及细胞周期蛋白D1

促进细胞增殖、迁移；与患者不良预后相关

[ 33- 34 ]

口腔鳞癌肿瘤干细胞

—

—

—

与患者较短的无病生存期有关

[27]

胰腺癌肿瘤干细胞

剪接因子

—

形成PAF1-PHF5A-DDX3亚复合体, 定位于Nanog启动子区域，增加肿瘤干细胞多能干细胞转录因子及干性标志物的表达以维持干性

促进肿瘤球、原位瘤及转移灶的形成

[24]

子宫内膜癌

剪接因子/辅

因子

Gjα1

在雌激素存在下，促进Gjα1 的表达

与子宫内膜腺癌发生可能有关

[26]

GBM干细胞

剪接因子

—

增强对富含C的3′端剪接位点外显子的识别

促进GBM干细胞增殖及异种移植瘤的发生发展

[35]

表 1  PHF5A在不同肿瘤中的调控作用及生物学功能
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