厦门大学学报（自然科学版）2025，Vol.64Issue(5)：747-758,12.DOI:10.6043/j.issn.0438-0479.202412017
锌指蛋白家族转录因子ZKSCAN3的生物功能及其作用机制的研究进展
Research progress on the biological functions and mechanisms of zinc finger protein family transcription factor ZKSCAN 3
摘要
Abstract
[Background]ZKSCAN3 is a zinc finger transcription factor located on chromosome 6(6p22.1),belonging to the C2H2-type zinc finger protein family.Its structure comprises a KRAB domain,a SCAN domain,and zinc finger motifs,which confer diverse biological functions.As the primary transcriptional repressor of autophagy,silencing ZKSCAN3 induces autophagy and enhances lysosomal biogenesis,processes critical for cellular homeostasis.ZKSCAN3 also plays significant roles in regulating cellular growth,motility,angiogenesis,and protein catabolism.Specifically,it maintains heterochromatin stability by interacting with nuclear envelope proteins and heterochromatin-associated proteins.This interaction enhances genomic stability and suppresses the expression of repetitive elements,which is essential for preserving stable gene expression and preventing aberrant gene activation.Furthermore,ZKSCAN3 modulates cellular proliferation,division,and signaling pathways by binding to specific sequences on chromosomal DNA,thereby influencing the activity of downstream genes.[Progress]ZKSCAN3 participates in diverse cellular regulations,playing critical roles in multiple physiological processes through direct or indirect modulation of gene expression,epigenetic modifications,and cellular signaling pathways.However,its functions vary across cell types,involving B-cell function,erythropoiesis,stem cell homeostasis,cardiomyocyte remodeling,autophagy regulation,and metabolic balance.Specifically,ZKSCAN3 exerts a crucial balancing effect on humoral immune responses and may act as a negative regulator of B-cell function.ZKSCA N3 gene knockout mice exhibit increased plasma cell numbers.Additionally,ZKSCAN3 expression is downregulated in mesenchymal stem cells(MSCs)derived from patients with Hutchinson-Gilford progeria syndrome,replicatively senescent MSCs,and primary MSCs isolated from elderly individuals,suggesting a potential link to aging regulation.Further studies demonstrate that ZKSCAN3 delays human stem cell senescence in an autophagy-independent manner by stabilizing interactions between nuclear envelope proteins and heterochromatin,thereby enhancing genomic stability and suppressing repetitive element expression.In addition to its role in normal cells,the biological functions of ZKSCAN3 in tumor cells have also garnered significant attention.In cancer,ZKSCAN3 regulates critical gene expression programs and plays important roles in the development,metastasis,and pathogenesis of various tumors,including hepatocellular carcinoma,gastric cancer,breast cancer,cervical cancer,prostate cancer,pancreatic cancer,bladder cancer,epithelial ovarian cancer,and multiple myeloma.Overexpression of ZKSCAN3 promotes tumor cell growth,while its knockout leads to growth arrest and accelerated senescence.Moreover,ZKSCAN3 represses a suite of genes associated with autophagy and lysosomal biogenesis.Beyond oncology,the role of ZKSCAN3 in other pathological processes is widely recognized.It influences disease progression in Parkinson's disease,spinal and bulbar muscular atrophy,acute pancreatitis,acute lung injury,and sepsis by regulating autophagy-lysosomal function,inflammatory responses,and cell death pathways.[Perspective]As a critical transcription factor,ZKSCAN3 has been extensively studied for its roles in tumor cell proliferation,senescence regulation,and humoral immune responses.Nevertheless,numerous underlying mechanisms remain to be elucidated.Future research should focus on developing precisely targeted therapeutics against ZKSCAN3 and exploring its influence on tumor cell survival through the regulation of processes such as apoptosis and autophagy.Furthermore,in-depth investigation into the specific mechanisms of ZKSCAN 3 in different cancer types,including its regulation of cellular proliferation,migration,and invasion,is warranted.Elucidating its interactions with other signaling pathways and assessing its potential to enhance cancer therapeutic efficacy are also key research priorities.Although progress has been made in studying ZKSCAN 3 in tumor cell lines and model organisms,its biological functions in diploid cells,such as normal human stem cells,require further exploration.Specific mechanisms,including the potential impact of ZKSCAN3 on erythrocyte survival equilibrium via its regulation of Tiam1 gene transcription and its putative role in modulating B-cell function,remain poorly defined.The interactions between ZKSCAN3 and transcription factors such as TFE3 and TFEB,and their functional consequences,represent another critical area for future research.Therefore,while ZKSCAN3 holds promise as a therapeutic target for gene therapy,a deeper understanding of its mechanisms of action across different physiological states is essential for realizing its therapeutic applications.Future research will unveil the broader biological functions and molecular mechanisms of ZKSCAN3,providing novel insights and approaches for the prevention and treatment of related diseases.关键词
ZKSCAN3/生物功能/作用机制/锌指蛋白Key words
ZKSCAN3/bio logical function/functional mechanism/zinc finger protein分类
生物科学引用本文复制引用
李文芳,徐建雄,苏正定..锌指蛋白家族转录因子ZKSCAN3的生物功能及其作用机制的研究进展[J].厦门大学学报（自然科学版）,2025,64(5):747-758,12.基金项目
国家自然科学基金(32471260) （32471260）
2024级校级大学生创新创业计划项目(XJU-SRT-24095) （XJU-SRT-24095）
