Research Progress on m6A Methylation in Endometrial Cancer

doi:10.12280/gjfckx.20250231

Abstract

Abstract:

Endometrial cancer (EC), as one of the three major malignant tumors in the female reproductive system, shows an increasing trend in incidence and mortality globally. Patients with early-stage EC have a favorable prognosis, but the survival time of those with advanced-stage and recurrent EC is significantly shortened. N6-methyladenosine (m⁶A) methylation is the most abundant epitranscriptomic modification in eukaryotic RNA, and the metabolism of RNA is dynamically regulated by three types of regulatory factors: methyltransferases, demethylases, and m⁶A-binding proteins. Studies have shown that abnormal expression of these regulatory factors plays a critical role in the pathogenesis and progression of EC. For instance, methyltransferase like 3 (METTL3) activates the protein kinase B (Akt) signaling pathway, and Wilms′ tumor 1-associating protein (WTAP) enhances the characteristics of EC stem cells by affecting the early growth response gene 1 (EGR1)/PTEN pathway. Fat mass and obesity-associated protein (FTO) and AlkB homolog 5 (ALKBH5) promote the proliferation and invasion of EC cells through signaling pathways such as phosphoinositide 3-kinase (PI3K)/Akt and by regulating the expression of insulin-like growth factor 1 receptor (IGF1R), respectively. In addition, YTH m⁶A RNA-binding protein 2 (YTHDF2) and IGF2 mRNA binding protein (IGF2BP) also participate in the regulation of the malignant phenotypes of EC cells. These findings provide novel perspectives for the early diagnosis and precise therapy of EC. In terms of diagnosis and treatment, high expression of proteins such as METTL3, METTL14, and FTO indicates a poor prognosis, while YTHDF2 is a potential biomarker for identifying precancerous lesions. Furthermore, overexpression of METTL3 can activate CD8+ T cells to inhibit the proliferation of EC, and the METTL3/FGD5-AS1 axis mediates paclitaxel resistance, which lays a theoretical foundation for the immunotherapy of EC and the improvement of chemotherapy resistance.

Key words: Methylation, Endometrial neoplasms, Therapy, Disease progression, m⁶A methylation, Pathogenesis

SI Cai-xia, CHENG Yue, SUN Ren-lian, XU Fei-xue. Research Progress on m⁶A Methylation in Endometrial Cancer[J]. Journal of International Obstetrics and Gynecology, 2025, 52(4): 414-419.

References 35

[1]	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3):229-263. doi: 10.3322/caac.21834.
[2]	Crosbie EJ, Kitson SJ, McAlpine JN, et al. Endometrial cancer[J]. Lancet, 2022, 399(10333):1412-1428. doi: 10.1016/S0140-6736(22)00323-3. pmid: 35397864
[3]	Baker-Rand H, Kitson SJ. Recent Advances in Endometrial Cancer Prevention, Early Diagnosis and Treatment[J]. Cancers(Basel), 2024, 16(5):1028. doi: 10.3390/cancers16051028.
[4]	Pilala KM, Panoutsopoulou K, Papadimitriou MA, et al. Exploring the methyl-verse: Dynamic interplay of epigenome and m⁶A epitranscriptome[J]. Mol Ther, 2025, 33(2):447-464. doi: 10.1016/j.ymthe.2024.12.003.
[5]	Mu S, Zhao K, Zhong S, et al. The Role of m6A Methylation in Tumor Immunity and Immune-Associated Disorder[J]. Biomolecules, 2024, 14(8):1042. doi: 10.3390/biom14081042.
[6]	Fang F, Wang P, Huang H, et al. m⁶A RNA methylation regulator-based signature for prognostic prediction and its potential immunological role in uterine corpus endometrial carcinoma[J]. BMC Cancer, 2022, 22(1):1364. doi: 10.1186/s12885-022-10490-x. pmid: 36581816
[7]	Fang Z, Mei W, Qu C, et al. Role of m6A writers, erasers and readers in cancer[J]. Exp Hematol Oncol, 2022, 11(1):45. doi: 10.1186/s40164-022-00298-7. pmid: 35945641
[8]	Su X, Lu R, Qu Y, et al. Methyltransferase-like 3 mediated RNA m⁶A modifications in the reproductive system: Potentials for diagnosis and therapy[J]. J Cell Mol Med, 2024, 28(4):e18128. doi: 10.1111/jcmm.18128.
[9]	Huang Q, Mo J, Liao Z, et al. The RNA m⁶A writer WTAP in diseases: structure, roles, and mechanisms[J]. Cell Death Dis, 2022, 13(10):852. doi: 10.1038/s41419-022-05268-9. pmid: 36207306
[10]	Huang J, Guo J, Jia R. N6-Methyladenosine Methyltransferase Component KIAA1429 Is a Potential Target of Cancer Therapy[J]. Biomolecules, 2024, 14(10):1319. doi: 10.3390/biom14101319.
[11]	Wang S, Liu Q. Research progress on m6A demethylase FTO and its role in gynecological tumors[J]. Front Oncol, 2024, 14:1413505. doi: 10.3389/fonc.2024.1413505.
[12]	Fang M, Ye L, Zhu Y, et al. M6A Demethylase ALKBH5 in Human Diseases: From Structure to Mechanisms[J]. Biomolecules, 2025, 15(2):157. doi: 10.3390/biom15020157.
[13]	Liao J, Wei Y, Liang J, et al. Insight into the structure, physiological function, and role in cancer of m6A readers-YTH domain-containing proteins[J]. Cell Death Discov, 2022, 8(1):137. doi: 10.1038/s41420-022-00947-0. pmid: 35351856
[14]	Zhu TY, Hong LL, Ling ZQ. Correction: Oncofetal protein IGF2BPs in human cancer: functions, mechanisms and therapeutic potential[J]. Biomark Res, 2023, 11(1):72. doi: 10.1186/s40364-023-00512-6.
[15]	Öz H, Canacankatan N, Antmen ŞE, et al. ′Investigation of miRNAs That Affect the PI3K/AKT/mTOR Signaling Pathway in Endometrial Cancer′[J]. Cell Biochem Biophys, 2025 Feb 21. doi: 10.1007/s12013-025-01694-6. Epub ahead of print.
[16]	Liu J, Eckert MA, Harada BT, et al. m⁶A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer[J]. Nat Cell Biol, 2018, 20(9):1074-1083. doi: 10.1038/s41556-018-0174-4.
[17]	Ruan P, Wang S, Yang C, et al. m⁶A mRNA methylation regulates the ERK/NF-κB/AKT signaling pathway through the PAPPA/IGFBP4 axis to promote proliferation and tumor formation in endometrial cancer[J]. Cell Biol Toxicol, 2023, 39(4):1611-1626. doi: 10.1007/s10565-022-09751-z.
[18]	赵满英, 伍东月, 杜瑞亭, 等. METTL14介导ERα的m6A修饰调控子宫内膜癌转移的机制研究[J]. 中国癌症杂志, 2023, 33(3):250-259. doi: 10.19401/j.cnki.1007-3639.2023.03.008.
[19]	Wang Y, Wang C, Guan X, et al. PRMT3-Mediated Arginine Methylation of METTL14 Promotes Malignant Progression and Treatment Resistance in Endometrial Carcinoma[J]. Adv Sci(Weinh), 2023, 10(36):e2303812. doi: 10.1002/advs.202303812.
[20]	Li Q, Wang C, Dong W, et al. WTAP facilitates progression of endometrial cancer via CAV-1/NF-κB axis[J]. Cell Biol Int, 2021, 45(6):1269-1277. doi: 10.1002/cbin.11570. pmid: 33559954
[21]	Wang B, Wang Y, Wang W, et al. WTAP/IGF2BP3 mediated m6A modification of the EGR1/PTEN axis regulates the malignant phenotypes of endometrial cancer stem cells[J]. J Exp Clin Cancer Res, 2024, 43(1):204. doi: 10.1186/s13046-024-03120-w. pmid: 39044249
[22]	Azzam SK, Alsafar H, Sajini AA. FTO m6A Demethylase in Obesity and Cancer: Implications and Underlying Molecular Mechanisms[J]. Int J Mol Sci, 2022, 23(7):3800. doi: 10.3390/ijms23073800.
[23]	Zhang L, Wan Y, Zhang Z, et al. FTO demethylates m6A modifications in HOXB13 mRNA and promotes endometrial cancer metastasis by activating the WNT signalling pathway[J]. RNA Biol, 2021, 18(9):1265-1278. doi: 10.1080/15476286.2020.1841458.
[24]	Pu X, Gu Z, Gu Z. ALKBH5 regulates IGF1R expression to promote the Proliferation and Tumorigenicity of Endometrial Cancer[J]. J Cancer, 2020, 11(19):5612-5622. doi: 10.7150/jca.46097. pmid: 32913456
[25]	Chen G, Liu B, Yin S, et al. Hypoxia induces an endometrial cancer stem-like cell phenotype via HIF-dependent demethylation of SOX2 mRNA[J]. Oncogenesis, 2020, 9(9):81. doi: 10.1038/s41389-020-00265-z. pmid: 32913192
[26]	Hong L, Pu X, Gan H, et al. YTHDF2 inhibit the tumorigenicity of endometrial cancer via downregulating the expression of IRS1 methylated with m⁶A[J]. J Cancer, 2021, 12(13):3809-3818. doi: 10.7150/jca.54527.
[27]	Qian Y, Chen H, Miao P, et al. Integrated Identification and Immunotherapy Response Analysis of the Prognostic Signature Associated With m6A, Cuproptosis-Related, Ferroptosis-Related lncRNA in Endometrial Cancer[J]. Cancer Rep(Hoboken), 2024, 7(9):e70009. doi: 10.1002/cnr2.70009.
[28]	Shen J, Feng XP, Hu RB, et al. N-methyladenosine reader YTHDF2-mediated long noncoding RNA FENDRR degradation promotes cell proliferation in endometrioid endometrial carcinoma[J]. Lab Invest, 2021, 101(6):775-784. doi: 10.1038/s41374-021-00543-3. pmid: 33692441
[29]	Zhang L, Wan Y, Zhang Z, et al. IGF2BP1 overexpression stabilizes PEG10 mRNA in an m6A-dependent manner and promotes endometrial cancer progression[J]. Theranostics, 2021, 11(3):1100-1114. doi: 10.7150/thno.49345. pmid: 33391523
[30]	Shi R, Zhao R, Shen Y, et al. IGF2BP2-modified circular RNA circCHD7 promotes endometrial cancer progression via stabilizing PDGFRB and activating JAK/STAT signaling pathway[J]. Cancer Gene Ther, 2024, 31(8):1221-1236. doi: 10.1038/s41417-024-00781-9.
[31]	Ralser DJ, Condic M, Klümper N, et al. Comprehensive immunohistochemical analysis of N6-methyladenosine (m6A) writers, erasers, and readers in endometrial cancer[J]. J Cancer Res Clin Oncol, 2023, 149(6):2417-2424. doi: 10.1007/s00432-022-04083-1.
[32]	Bian PP, Liu SY, Luo QP, et al. YTHDF2 is a novel diagnostic marker of endometrial adenocarcinoma and endometrial atypical hyperplasia/ intraepithelial neoplasia[J]. Pathol Res Pract, 2022, 234:153919. doi: 10.1016/j.prp.2022.153919.
[33]	Xiong Q, Zhang Y, Zheng Y, et al. Regulation and application of m⁶A modification in tumor immunity[J]. Sci China Life Sci, 2025, 68(4):974-993. doi: 10.1007/s11427-024-2648-0.
[34]	Zhan L, Zhang J, Zhang JH, et al. METTL3 facilitates immunosurveillance by inhibiting YTHDF2-mediated NLRC5 mRNA degradation in endometrial cancer[J]. Biomark Res, 2023, 11(1):43. doi: 10.1186/s40364-023-00479-4. pmid: 37085864
[35]	Hao M, Li T, Xiao L, et al. METTL3-induced FGD5-AS1 contributes to the tumorigenesis and PD-1/PD-L1 checkpoint to enhance the resistance to paclitaxel of endometrial carcinoma[J]. J Cell Mol Med, 2024, 28(5):e17971. doi: 10.1111/jcmm.17971.

Research Progress on m⁶A Methylation in Endometrial Cancer

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References 35

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	WANG Xin-yi, SUN Li-zhou, JIANG Zi-yan. A Case of Late Pregnancy Complicated with Congenital Factor Ⅺ Deficiency [J]. Journal of International Obstetrics and Gynecology, 2026, 53(3): 267-269.
[2]	ZHENG Xiao-lin, WEI Fang. Research Progress on LPCAT1 in Gynecological Malignancies [J]. Journal of International Obstetrics and Gynecology, 2026, 53(3): 273-277.
[3]	HE Qian-nan, HUANG Zi-jie, WANG Yi-fan, AN Yu-sheng, FENG Shu-xian. Research Progress on Dual-Gene Methylation Testing of PAX1/JAM3 in Management of Cervical Lesion [J]. Journal of International Obstetrics and Gynecology, 2026, 53(3): 278-284.
[4]	XIANG Xiao-ying, SUN Ya-ge, ZHANG Yun-feng, JIA Han, WANG Yue. Research Advances in the Immune Microenvironment and Immunotherapy for p53-Abnormal Endometrial Carcinoma [J]. Journal of International Obstetrics and Gynecology, 2026, 53(3): 285-291.
[5]	WANG Wei, DAI Bai, SHA Ri-na, TUO Ya. Analysis of the Role and Molecular Subtype Association of Kinesin Family Member 18B in Endometrial Carcinoma [J]. Journal of International Obstetrics and Gynecology, 2026, 53(3): 292-297.
[6]	WU Hua-tuo, HUANG Chun-lin, MA Yan, GE Ting, LI Li. Research Progress on the Immune Microenvironment of Ovarian Cancer [J]. Journal of International Obstetrics and Gynecology, 2026, 53(3): 297-301.
[7]	ZHENG Le, ZHANG Xin, JIA Hai-qing. A Case Report of Pulmonary Metastasis from Placental Site Trophoblastic Tumor Treated with Chemotherapy Combined with Thoracoscopic Surgery [J]. Journal of International Obstetrics and Gynecology, 2026, 53(3): 302-305.
[8]	YIN Di-shuang, LI Nan, GUO Hong-xia. Collision Tumor Composed of High-Grade Endometrial Stromal Sarcoma and Endometrioid Adenocarcinoma: A Case Report [J]. Journal of International Obstetrics and Gynecology, 2026, 53(3): 311-317.
[9]	LIU Er-yu, REN Qing-yu, GAO Xiang. A Case of Recurrent Cervical Cancer with Vesicoenteric Fistula [J]. Journal of International Obstetrics and Gynecology, 2026, 53(3): 322-328.
[10]	YANG Yan, YAN Kai, ZHOU Deng-lian, DENG Xin. Exosomes in Endometrial Fibrosis: Mechanisms and Potential Diagnostic and Therapeutic Applications [J]. Journal of International Obstetrics and Gynecology, 2026, 53(3): 335-340.
[11]	XIAO Jin-fen, ZHANG Xu-mei, LIU Yi, ZENG Qian, ZHANG Wen-ying. Impaired β-hCG Clearance Due to End-Stage Renal Disease: A Case Report [J]. Journal of International Obstetrics and Gynecology, 2026, 53(3): 357-360.
[12]	LIU Meng-ting, YAO Shun, DING Jin. Research Progress on Mesenchymal Stem Cell Therapy for Stress Urinary Incontinence [J]. Journal of International Obstetrics and Gynecology, 2026, 53(2): 121-124.
[13]	ZHANG Chun-jie, WU Li-xian, YANG Bo, LIU Zhi-jie, ZHENG Jing. A Case of Atypical McCune-Albright Syndrome in A Prepubertal Girl [J]. Journal of International Obstetrics and Gynecology, 2026, 53(2): 150-152.
[14]	XU Meng-ting, LU Di, SONG Dian-rong. Research Progress in the Tumor Microenvironment of Ovarian Cancer [J]. Journal of International Obstetrics and Gynecology, 2026, 53(2): 188-193.
[15]	ZHANG Yan, SONG Shu-fang. Advances in the Application of DNA Methylation in Cervical Lesions [J]. Journal of International Obstetrics and Gynecology, 2026, 53(2): 206-210.