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组蛋白H3K27me3修饰缺失上调弥漫型胃癌细胞中
SLC7A11 的表达Loss of histone H3K27me3 up-regulates SLC7A11 in diffuse gastric cancer cells
- 陆军军医大学学报 2025年47卷第1期 页码：71-81
- 作者机构：
陆军特色医学中心（第三军医大学大坪医院）消化内科，消化系统肿瘤精准防治重庆市重点实验室，重庆
- 作者简介：
王斌，E-mail： wb_tmmu@126.com
杨敏，E-mail： yangmindoctor@126.com
- 基金信息：基金项目：国家重点研发计划(2022YFA1105302;2023YFC3402102)
DOI：10.16016/j.2097-0927.202406068
中图分类号： R394.3;R730.23;R735.2纸质出版日期：2025-01-15，
收稿日期：2024-06-20，
修回日期：2024-10-18，
- 稿件说明：
移动端阅览
任原锋,刘文康,储召乐,等.组蛋白H3K27me3修饰缺失上调弥漫型胃癌细胞中SLC7A11的表达[J].陆军军医大学学报,2025,47(01):71-81.
REN Yuanfeng,LIU Wenkang,CHU Zhaole,et al.Loss of histone H3K27me3 up-regulates SLC7A11 in diffuse gastric cancer cells[J].J Army Med Univ,2025,47(1):71-81.
任原锋,刘文康,储召乐,等.组蛋白H3K27me3修饰缺失上调弥漫型胃癌细胞中SLC7A11的表达[J].陆军军医大学学报,2025,47(01):71-81. DOI：10.16016/j.2097-0927.202406068.
REN Yuanfeng,LIU Wenkang,CHU Zhaole,et al.Loss of histone H3K27me3 up-regulates SLC7A11 in diffuse gastric cancer cells[J].J Army Med Univ,2025,47(1):71-81. DOI：10.16016/j.2097-0927.202406068.
摘要
目的
2
描绘弥漫型胃癌组织中组蛋白H3第27位赖氨酸的三甲基化（H3K27me3）修饰的全基因组分布图谱，通过鉴定H3K27me3所调控的关键靶基因，初步探究H3K27me3修饰重编程可能调控弥漫型胃癌细胞发生发展的作用机制。
方法
2
样本来源于2021-2023年在陆军特色医学中心消化内科内镜中心及手术室胃肠外科组接受检查或治疗的患者。共收集到正常组患者14例，其中男性6例，女性8例，平均年龄46岁；胃癌组患者14例，其中男性8例，女性6例，平均年龄63岁。采用染色质靶向剪切及转座酶技术（cleavage under target and tagmentation， CUT&Tag）捕获基因组H3K27me3修饰区域，分析H3K27me3修饰重编程特征。整合转录组（RNA‐Seq）测序数据、高通量染色体构象捕获技术（high‐throughput chromosome conformation capture，Hi‐C）及已发表的公共单细胞数据，分析H3K27me3修饰重编程在弥漫型胃癌细胞中所调控靶基因。
结果
2
CUT
&
Tag和RNA测序数据质量符合下游分析标准，正常胃黏膜组织和弥漫型胃癌组织的组蛋白H3K27me3修饰均主要分布于远端基因间区和内含子区。相较于正常组织，胃癌组织的H3K27me3修饰存在显著的重编程特征，表现为H3K27me3总体信号强度明显降低。其中缺失的2 912个H3K27me3信号峰可能导致822个肿瘤相关基因的表达上调，这些基因中上调最显著（信号值强度的差异倍数≥2，
P
<
0.05）的56个基因主要富集于哺乳动物雷帕霉素靶蛋白复合体1（mammalian target of rapamycin complex 1，mTORC1）信号通路，其中甲硫氨酸转运体
SLC7A5
和胱氨酸转运体
SLC7A11
在胃癌组织中的表达最高。单细胞数据提示，弥漫型胃癌组织中
SLC7A11
的异常高表达主要存在于肿瘤上皮细胞。利用公共数据和免疫组织化学实验进一步验证
SLC7A11
在弥漫型胃癌中高表达，且与胃癌患者的不良预后相关。
结论
2
组蛋白H3K27me3修饰重编程是弥漫型胃癌的重要表观遗传学特征；组蛋白H3K27me3修饰缺失可能上调肿瘤细胞
SLC7A11
表达，进而促进肿瘤进展。
Abstract
Objective To map the genome-wide distribution profile of histone H3K27me3 modification in diffuse gastric cancer tissues， identify target genes regulated by H3K27me3， and primarily explore the potential mechanism of its modification reprogramming in the occurrence and development of the tumor. Methods Normal gastric mucosal tissues and diffuse gastric cancer tissues were harvested from the patients who underwent examinations or treatments in the departments of gastroenterology and gastrointestinal surgery of our medical center between 2021 and 2023. There were 14 patients in the normal group （6 males and 8 females， average age of 46 years） and 14 patients in the gastric cancer group （8 males and 6 females， average age of 63 years）. Cleavage under target and tagmentation （CUT
&
Tag） technology was employed to capture genomic regions modified by H3K27me3， and analyze the reprogramming characteristics of these modifications. RNA sequencing data， data from high-throughput chromosome conformation capture （Hi-C） technology， and publicly available single-cell data were integrated to investigate the target genes regulated by the reprogramming of H3K27me3 modifications in diffuse gastric cancer cells. Results The quality of the CUT
&
Tag and RNA sequencing data met the standards required for subsequent analysis. Histone H3K27me3 modifications in normal gastric mucosa and diffuse gastric cancer tissues were primarily distributed in distal intergenic regions and intronic regions. In gastric cancer tissues， compared to normal tissues， there was significant reprogramming of H3K27me3 modifications， characterized by a marked reduction in overall H3K27me3 signal intensity. The loss of 2 912 H3K27me3 signal peaks might lead to the up-regulation of 822 tumor-associated genes. Among them， 56 genes displayed the most significant up-regulation （fold change in signal intensity ≥2，
P
<
0.05），
with notable enrichment in the mammalian target of rapamycin complex 1 （mTORC1） signaling pathway. Specifically， the methionine transporter
SLC7A5
and the cystine transporter
SLC7A11
were found to have the highest expression levels in gastric cancer tissues. Single-cell data revealed that the abnormal overexpression of
SLC7A11
in diffuse gastric cancer was primarily observed in tumor epithelial cells. Further validation using public data and immunohistochemical experiments confirmed the elevated expression of
SLC7A11
in diffuse gastric cancer， which is associated with poor prognosis in gastric cancer patients. Conclusion The reprogramming of histone H3K27me3 modification is an important epigenetic characteristic in diffuse gastric cancer. Loss of H3K27me3 signal peaks may up-regulate the expression of
SLC7A11
in diffuse gastric cancer cells， and thereby promote tumor progression.
关键词
H3K27me3组蛋白修饰表观遗传弥漫型胃癌溶质载体家族7A11
Keywords
H3K27me3histone modificationepigeneticsdiffuse gastric cancerSLC7A11
references
SUNG H， FERLAY J， SIEGEL R L， et al. Global cancer statistics 2020： GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries［J］. CA Cancer J Clin， 2021， 71（3）： 209-249. DOI： 10.3322/caac.21660http://dx.doi.org/10.3322/caac.21660.
LAUREN P. The two histological main types of gastric carcinoma： diffuse and so-called intestinal-type carcinoma. an attempt at a histo-clinical classification［J］. Acta Pathol Microbiol Scand， 1965， 64： 31-49. DOI： 10.1111/apm.1965.64.1.31http://dx.doi.org/10.1111/apm.1965.64.1.31.
HENSON D E， DITTUS C， YOUNES M， et al. Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States， 1973-2000： increase in the signet ring cell type［J］. Arch Pathol Lab Med， 2004， 128（7）： 765-770. DOI： 10.5858/2004-128-765-DTITIAhttp://dx.doi.org/10.5858/2004-128-765-DTITIA.
CHEN Y C， FANG W L， WANG R F， et al. Clinicopathological variation of lauren classification in gastric cancer［J］. Pathol Oncol Res， 2016， 22（1）： 197-202. DOI： 10.1007/s12253-015-9996-6http://dx.doi.org/10.1007/s12253-015-9996-6.
CHIA N Y， TAN P. Molecular classification of gastric cancer［J］. Ann Oncol， 2016， 27（5）： 763-769. DOI： 10.1093/annonc/mdw040http://dx.doi.org/10.1093/annonc/mdw040.
ZHANG Q， CAO X T. Epigenetic remodeling in innate immunity and inflammation［J］. Annu Rev Immunol， 2021， 39： 279-311. DOI： 10.1146/annurev-immunol-093019-123619http://dx.doi.org/10.1146/annurev-immunol-093019-123619.
HO S W T， SHENG T T， XING M J， et al. Regulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities［J］. Gut， 2023， 72（2）： 226-241. DOI： 10.1136/gutjnl-2021-326483http://dx.doi.org/10.1136/gutjnl-2021-326483.
陈旭， 储召乐， 秦苾珺， 等. 增强子及相关调控组在肠型胃癌中的重塑特征及其预后预测模型［J］. 陆军军医大学学报， 2024， 46（7）： 695-704. DOI： 10.16016/j.2097-0927.202309147http://dx.doi.org/10.16016/j.2097-0927.202309147.
CHEN X， CHU Z L， QIN B J， et al. Remodeling characteristics and construction of a survival prediction model based on enhancers and regulome in intestinal type gastric cancer［J］. J Army Med Univ， 2024， 46（7）： 695-704. DOI： 10.16016/j.2097-0927.202309147http://dx.doi.org/10.16016/j.2097-0927.202309147.
刘文康， 吴林育， 喻博， 等. 胃黏膜肠上皮化生的H3K27ac增强子重编程特征及转录调控机制［J］. 陆军军医大学学报， 2023， 45（6）： 500-509. DOI： 10.16016/j.2097-0927.202210071http://dx.doi.org/10.16016/j.2097-0927.202210071.
LIU W K， WU L Y， YU B， et al. Reprogramming characteristics of H3K27ac-marked enhancer in gastric intestinal metaplasia and its transcriptional regulatory mechanism［J］. J Army Med Univ， 2023， 45（6）： 500-509. DOI： 10.16016/j.2097-0927.202210071http://dx.doi.org/10.16016/j.2097-0927.202210071.
ZHANG Y Z， YUAN J L， ZHANG L R， et al. Coupling of H3K27me3 recognition with transcriptional repression through the BAH-PHD-CPL2 complex in Arabidopsis［J］. Nat Commun， 2020， 11（1）： 6212. DOI： 10.1038/s41467-020-20089-0http://dx.doi.org/10.1038/s41467-020-20089-0.
吴林育. 胃黏膜肠化的H3K27me3沉默子重塑特征及肠化调控因子ATOH1的初步功能鉴定［D］. 陆军军医大学， 2023.
WU L Y. Remodeling characteristics of H3K27me3 silencing in intestinal metaplasia of gastric mucosa and preliminary functional identification of ATOH1， a regulator of intestinal metaplasia［D］. Army Medical University， 2023.
秦苾珺， 谭玉婷， 储召乐， 等. 组蛋白H3K27me3沉默子重塑上调胃黏膜高级别上皮内瘤变磷酸甘油醛激酶1表达［J］. 陆军军医大学学报， 2024， 46（6）： 597-607. DOI： 10.16016/j.2097-0927.202310001http://dx.doi.org/10.16016/j.2097-0927.202310001.
QIN B J， TAN Y T， CHU Z L， et al. Remodeling of histone H3K27me3-associated silencers upregulates PGK1 expression in gastric high-grade intraepithelial neoplasia［J］. J Army Med Univ， 2024， 46（6）： 597-607. DOI： 10.16016/j.2097-0927.202310001http://dx.doi.org/10.16016/j.2097-0927.202310001.
FLAVAHAN W A， GASKELL E， BERNSTEIN B E. Epigenetic plasticity and the hallmarks of cancer［J］. Science， 2017， 357（6348）： eaal2380. DOI： 10.1126/science.aal2380http://dx.doi.org/10.1126/science.aal2380.
CHEN S J， ZHANG J， ZHOU T， et al. Epigenetically upregulated NSUN2 confers ferroptosis resistance in endometrial cancer via m5C modification of SLC7A11 mRNA［J］. Redox Biol， 2024， 69： 102975. DOI： 10.1016/j.redox.2023.102975http://dx.doi.org/10.1016/j.redox.2023.102975.
CORCES M R， TREVINO A E， HAMILTON E G， et al. An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues［J］. Nat Methods， 2017， 14（10）： 959-962. DOI： 10.1038/nmeth.4396http://dx.doi.org/10.1038/nmeth.4396.
KAYA-OKUR H S， JANSSENS D H， HENIKOFF J G， et al. Efficient low-cost chromatin profiling with CUT&Tag［J］. Nat Protoc， 2020， 15（10）： 3264-3283. DOI： 10.1038/s41596-020-0373-xhttp://dx.doi.org/10.1038/s41596-020-0373-x.
TU S Q， LI M S， CHEN H J， et al. MAnorm2 for quantitatively comparing groups of ChIP-seq samples［J］. Genome Res， 2021， 31（1）： 131-145. DOI： 10.1101/gr.262675.120http://dx.doi.org/10.1101/gr.262675.120.
ZHOU R W， XU J， MARTIN T C， et al. A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma［J］. Nat Commun， 2022， 13： 6041. DOI： 10.1038/s41467-022-33377-8http://dx.doi.org/10.1038/s41467-022-33377-8.
ZHAO W Z， JIA Y F， SUN G Y， et al. Single-cell analysis of gastric signet ring cell carcinoma reveals cytological and immune microenvironment features［J］. Nat Commun， 2023， 14（1）： 2985. DOI： 10.1038/s41467-023-38426-4http://dx.doi.org/10.1038/s41467-023-38426-4.
LIU X Y， WANG C F， LIU W Q， et al. Distinct features of H3K4me3 and H3K27me3 chromatin domains in pre-implantation embryos［J］. Nature， 2016， 537（7621）： 558-562. DOI： 10.1038/nature19362http://dx.doi.org/10.1038/nature19362.
KOPPULA P， ZHUANG L， GAN B Y. Cystine transporter SLC7A11/xCT in cancer： ferroptosis， nutrient dependency， and cancer therapy［J］. Protein Cell， 2021， 12（8）： 599-620. DOI： 10.1007/s13238-020-00789-5http://dx.doi.org/10.1007/s13238-020-00789-5.
KANAI Y. Amino acid transporter LAT1 （SLC7A5） as a molecular target for cancer diagnosis and therapeutics［J］. Pharmacol Ther， 2022， 230： 107964. DOI： 10.1016/j.pharmthera.2021.107964http://dx.doi.org/10.1016/j.pharmthera.2021.107964.
DE VISSER K E， JOYCE J A. The evolving tumor microenvironment： From cancer initiation to metastatic outgrowth［J］. Cancer Cell， 2023， 41（3）： 374-403. DOI： 10.1016/j.ccell.2023.02.016http://dx.doi.org/10.1016/j.ccell.2023.02.016.
CRISTESCU R， LEE J， NEBOZHYN M， et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes［J］. Nat Med， 2015， 21（5）： 449-456. DOI： 10.1038/nm.3850http://dx.doi.org/10.1038/nm.3850.
KIM T S， DA SILVA E， COIT D G， et al. Intratumoral immune response to gastric cancer varies by molecular and histologic subtype［J］. Am J Surg Pathol， 2019， 43（6）： 851-860. DOI： 10.1097/PAS.0000000000001253http://dx.doi.org/10.1097/PAS.0000000000001253.
YAMAMOTO E， SUZUKI H， TAKAMARU H， et al. Role of DNA methylation in the development of diffuse-type gastric cancer［J］. Digestion， 2011， 83（4）： 241-249. DOI： 10.1159/000320453http://dx.doi.org/10.1159/000320453.
LIU X D. SLC family transporters［J］. Adv Exp Med Biol， 2019， 1141： 101-202. DOI： 10.1007/978-981-13-7647-4_3http://dx.doi.org/10.1007/978-981-13-7647-4_3.
ZHOU S W， SHU Y. Transcriptional regulation of solute carrier （SLC） drug transporters［J］. Drug Metab Dispos， 2022， 50（9）： 1238-1250. DOI： 10.1124/dmd.121.000704http://dx.doi.org/10.1124/dmd.121.000704.
CÉSAR-RAZQUIN A，SNIJDER B，FRAPPIER-BRINTON T， et al. A call for systematic research on solute carriers［J］. Cell， 2015， 162（3）： 478-487. DOI： 10.1016/j.cell. 2015.07.022http://dx.doi.org/10.1016/j.cell.2015.07.022.
CAO T Y， ZHANG W Y， WANG Q， et al. Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells［J］. Cell， 2024， 187（9）： 2288-2304.e27. DOI： 10.1016/j.cell. 2024.03.011http://dx.doi.org/10.1016/j.cell.2024.03.011.
GUO C S， YOU Z Y， SHI H， et al. SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity［J］. Nature， 2023， 620（7972）： 200-208. DOI： 10.1038/s41586-023-06299-8http://dx.doi.org/10.1038/s41586-023-06299-8.
HE F， ZHANG P， LIU J L， et al. ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 （xCT） to block stress-related ferroptosis［J］. J Hepatol， 2023， 79（2）： 362-377. DOI： 10.1016/j.jhep.2023.03.016http://dx.doi.org/10.1016/j.jhep.2023.03.016.
ZHOU Q Y， YU H F， CHEN Y X， et al. The CRL3KCTD10 ubiquitin ligase-USP18 axis coordinately regulates cystine uptake and ferroptosis by modulating SLC7A11［J］. Proc Natl Acad Sci U S A， 2024， 121（28）： e2320655121. DOI： 10.1073/pnas.2320655121http://dx.doi.org/10.1073/pnas.2320655121.
CHEN Q P， ZHENG W， GUAN J， et al. SOCS2-enhanced ubiquitination of SLC7A11 promotes ferroptosis and radiosensitization in hepatocellular carcinoma［J］. Cell Death Differ， 2023， 30（1）： 137-151. DOI： 10.1038/s41418-022-01051-7http://dx.doi.org/10.1038/s41418-022-01051-7.
WANG Z J， SHEN N， WANG Z A， et al. TRIM3 facilitates ferroptosis in non-small cell lung cancer through promoting SLC7A11/xCT K11-linked ubiquitination and degradation［J］. Cell Death Differ， 2024， 31（1）： 53-64. DOI： 10.1038/s41418-023-01239-5http://dx.doi.org/10.1038/s41418-023-01239-5.
王磊， 万凌红， 王涛， 等. 新辅助免疫化疗对比新辅助化疗用于局部进展期胃癌的临床疗效分析 ［J］. 陆军军医大学学报， 2024， 46（20）： 2313-2321. DOI：10.16016/j.2097-0927.202405076http://dx.doi.org/10.16016/j.2097-0927.202405076.
WANG L，WAN L H，WANG T，et al. Clinical efficacy of neoadjuvant immunochemotherapy versus neoadjuvant chemotherapy for local advanced gastric adenocarcinoma［J］. J Amry Med Univ，2024，46（20）：2313-2321.DOI：10.16016/j.2097-0927.202405076http://dx.doi.org/10.16016/j.2097-0927.202405076.
WANG L， WAN L H， CHEN X， et al. Reduced intestinal-to-diffuse conversion and immunosuppressive responses underlie superiority of neoadjuvant immunochemotherapy in gastric adenocarcinoma ［J］. MedComm， 2024， 5（11）： e762. DOI： 10.1002/mco2.762http://dx.doi.org/10.1002/mco2.762.
WANG L， SUN M T， LI J Y， et al. Intestinal subtype as a biomarker of response to neoadjuvant immunochemotherapy in locally advanced gastric adenocarcinoma： insights from a prospective phase II trial ［J］. Clin Cancer Res， 2025， 31（1）： 74-86. DOI： 10.1158/1078-0432.CCR-24-2436http://dx.doi.org/10.1158/1078-0432.CCR-24-2436.
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