Expression and clinical significance of KDM4C in colorectal cancer

doi:10.3877/cma.j.issn.2095-3224.2025.01.006

Abstract

Abstract:

Objective

To investigate the expression of KDM4C in colon cancer tissue and its clinical implications.

Methods

The expression of KDM4C in colon cancer was detected using immunohistochemistry.The relationship between KDM4C and clinical pathological factors as well as prognosis was analyzed.The expression status of KDM4C was also analyzed using TCGA database， and its relationship with survival prognosis was further investigated using the Kaplan-Meier method.Single-cell analysis from GSE108989 was performed to examine the distribution of KDM4C across various cell types.A quanTIseq approach was utilized to explore the correlation between KDM4C and immune cell infiltration in colon cancer.The effect of KDM4C on the proliferation and drug sensitivity of cancer cells was assessed using CCK-8 experiment.

Results

KDM4C expression in colon cancer tissues was higher than that in adjacent non-cancerous tissues （Z= -5.722， P＜0.001）.The expression of KDM4C was correlated with tumor size （χ²=6.473， P=0.011）， invasion depth （χ²=4.146， P=0.020）， lymph node metastasis （χ²=6.473， P=0.011），TNM staging （χ²=5.840， P=0.016）， and chemotherapy resistance （χ²=5.38， P=0.032）.TCGA database revealed significantly higher expression of KDM4C mRNA in colon cancer compared to normal colon mucosal tissue （Z= -2.297， P＜0.001）.Survival analysis indicated that patients with high KDM4C expression had a significantly lower overall survival rate compared to those with low expression， the difference being statistically significant.Subgroup analysis revealed that patients with high KDM4C expression in right-sided colon cancer had significantly lower overall survival compared to those with low expression，（χ²=4.691，P=0.0303）.Single-cell sequencing analysis of GSE108989 showed that KDM4C was expressed in CD4Tconv，CD8T， CD8Tex， Tprolif， and Treg cells.Immunoinfiltration analysis revealed that KDM4C expression was associated with infiltration by B cells， M2 macrophages， neutrophils， and Tregs.Downregulation of KDM4C expression inhibited the proliferation activity of colorectal cancer cells HCT116 and SW480， and enhanced their sensitivity to oxaliplatin.

Conclusion

High KDM4C expression is associated with poor survival prognosis in colon cancer.Downregulation of KDM4C can inhibit the proliferation of colorectal cancer cells，and enhance their chemosensitivity.

Key words: Colonic neoplasms, Lysine-specific demethylase 4C, Prognosis

Bing Zeng, Jinhong Li, Haiyang Xin, Fuheng Liu, Zhilong Yuan, Wenchang Gan, Canfeng Cai, Yingru Li. Expression and clinical significance of KDM4C in colorectal cancer[J]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2025, 14(01): 53-61.

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Figures/Tables 8

References 18

［1］	Wang Z， Zang C， Rosenfeld JA， et al.Combinatorial patterns of histone acetylations and methylations in the human genome［J］.Nat Genet，2008， 40（7）： 897-903.
［2］	Ye Q， Holowatyj A， Wu J， et al.Genetic alterations of KDM4 subfamily and therapeutic effect of novel demethylase inhibitor in breast cancer［J］.Am J Cancer Res， 2015， 5（4）： 1519-1530.
［3］	Lee HY， Yang EG， Park H.Hypoxia enhances the expression of prostate-specific antigen by modifying the quantity and catalytic activity of Jumonji C domain-containing histone demethylases［J］.Carcinogenesis， 2013， 34（12）： 2706-2715.
［4］	Yang D， Xu T， Fan L， et al.MicroRNA-216b enhances cisplatininduced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1alpha/HES1 signaling axis［J］.J Exp Clin Cancer Res， 2020， 39（1）： 201.
［5］	Xu Y， Yao HB， Jin Y， et al.Expressions of Jumonji domain containing protein 2C and hypoxia-inducible factor-1alpha in gastric carcinoma and their clinical significance［J］.Natl Med J China， 2013， 93（42）：3375-3378.
［6］	Liu G， Zhu J， Yu M， et al.Glutamate dehydrogenase is a novel prognostic marker and predicts metastases in colorectal cancer patients［J］.J Transl Med， 2015， 13： 144.
［7］	Katoh M， Katoh M.Identification and characterization of JMJD2 family genes in silico［J］.Int J Oncol， 2004， 24（6）： 1623-1628.
［8］	Cloos PA， Christensen J， Agger K， et al.The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3［J］.Nature， 2006， 442（7100）： 307-311.
［9］	Whetstine JR， Nottke A， Lan F， et al.Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases［J］.Cell，2006，125（3）： 467-481.
［10］	Pedersen MT， Agger K， Laugesen A， et al.The demethylase JMJD2C localizes to H3K4me3-positive transcription start sites and is dispensable for embryonic development［J］.Mol Cell Biol， 2014， 34（6）：1031-1045.
［11］	Ishimura A， Terashima M， Kimura H， et al.Jmjd2c histone demethylase enhances the expression of Mdm2 oncogene［J］.Biochem Biophys Res Commun， 2009， 389（2）： 366-371.
［12］	Yu Y， Schleich K， Yue B， et al.Targeting the senescence-overriding cooperative activity of structurally unrelated H3K9 demethylases in melanoma［J］.Cancer Cell， 2018， 33（4）： 785.
［13］	Kupershmit I， Khoury-Haddad H， Awwad SW， et al.KDM4C （GASC1）lysine demethylase is associated with mitotic chromatin and regulates chromosome segregation during mitosis［J］.Nucleic Acids Res， 2014，42（10）： 6168-6182.
［14］	Luo W， Chang R， Zhong J， et al.Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression［J］.Proc Natl Acad Sci USA， 2012， 109（49）： E3367-3376.
［15］	Li N， Jiang D.Jumonji domain containing 2C promotes cell migration and invasion through modulating CUL4A expression in lung cancer［J］.Biomed Pharmacother， 2017， 89： 305-315.
［16］	Wu X， Li R， Song Q， et al.JMJD2C promotes colorectal cancer metastasis via regulating histone methylation of MALAT1 promoter and enhancing beta-catenin signaling pathway［J］.J Exp Clin Cancer Res， 2022， 41（1）： 205.
［17］	Uimonen K， Merikallio H， Paakko P， et al.GASC1 expression in lung carcinoma is associated with smoking and prognosis of squamous cell carcinoma［J］.Histol Histopathol， 2014， 29（6）： 797-804.
［18］	Berdel B， Nieminen K， Soini Y， et al.Histone demethylase GASC1--a potential prognostic and predictive marker in invasive breast cancer［J］.BMC Cancer， 2012， 12： 516.

因素	KDM4C		χ ² 值	P 值
因素	低表达组（n=21）	高表达组（n=32）	χ ² 值	P 值
性别			0.535	0.465
男性	9（42.9）	17（53.1）
女性	12（57.1）	15（46.9）
年龄（岁）			0.260	0.291
＜50	2（22.2）	7（77.8）
≥ 50	19（43.2）	25（56.8）
术前CEA（ng/mL）			0.154	0.695
≤ 5	10（47.6）	17（53.1）
＞5	11（52.4）	15（46.9）
肿瘤部位			1.388	0.239
右半结肠	9（42.9）	19（59.4）
左半结肠	12（57.1）	13（40.6）
肿瘤大小（cm）			6.473	0.011
＜5	16（76.2）	13（40.6）
≥ 5	5（23.8）	19（59.4）
分化程度			1.716	0.190
高/ 中分化	20（95.2）	25（78.1）
低分化	1（4.8）	7（21.9）

因素	KDM4C		χ ² 值	P 值
因素	低表达组（n=21）	高表达组（n=32）	χ ² 值	P 值
性别			0.535	0.465
男性	9（42.9）	17（53.1）
女性	12（57.1）	15（46.9）
年龄（岁）			0.260	0.291
＜50	2（22.2）	7（77.8）
≥ 50	19（43.2）	25（56.8）
术前CEA（ng/mL）			0.154	0.695
≤ 5	10（47.6）	17（53.1）
＞5	11（52.4）	15（46.9）
肿瘤部位			1.388	0.239
右半结肠	9（42.9）	19（59.4）
左半结肠	12（57.1）	13（40.6）
肿瘤大小（cm）			6.473	0.011
＜5	16（76.2）	13（40.6）
≥ 5	5（23.8）	19（59.4）
分化程度			1.716	0.190
高/ 中分化	20（95.2）	25（78.1）
低分化	1（4.8）	7（21.9）

因素	KDM4C		χ ² 值	P 值
因素	低表达组（n=21）	高表达组（n=32）	χ ² 值	P 值
脉管神经侵犯			3.112	0.078
无	15（71.4）	15（46.9）
有	6（28.6）	17（53.1）
浸润深度			4.146	0.02
T1～T2	4（19.0）	0（0.0）
T3～T4	17（81.0）	32（100.0）
淋巴结转移			6.473	0.011
无	16（76.2）	13（40.6）
有	5（23.8）	19（59.4）
TNM 分期			5.840	0.016
Ⅰ ～ Ⅱ	15（71.4）	12（37.5）
Ⅲ ～ Ⅳ	6（28.6）	20（62.5）

因素	KDM4C		χ ² 值	P 值
因素	低表达组（n=21）	高表达组（n=32）	χ ² 值	P 值
脉管神经侵犯			3.112	0.078
无	15（71.4）	15（46.9）
有	6（28.6）	17（53.1）
浸润深度			4.146	0.02
T1～T2	4（19.0）	0（0.0）
T3～T4	17（81.0）	32（100.0）
淋巴结转移			6.473	0.011
无	16（76.2）	13（40.6）
有	5（23.8）	19（59.4）
TNM 分期			5.840	0.016
Ⅰ ～ Ⅱ	15（71.4）	12（37.5）
Ⅲ ～ Ⅳ	6（28.6）	20（62.5）

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