PCIF1 drives oesophageal squamous cell carcinoma progression via m6Am-mediated suppression of MTF2 translation

Abstract

Oesophageal squamous cell carcinoma (OSCC) represents a highly aggressive malignancy with limited therapeutic options and poor prognosis. This study uncovers PCIF1 as a critical driver of OSCC progression via m6Am RNA modification, leading to translational repression of the tumour suppressor MTF2. Our results demonstrate that PCIF1 selectively suppresses MTF2 translation, activating oncogenic pathways that promote OSCC growth. In vitro and in vivo models confirm that PCIF1 knockdown reduces OSCC progression, whereas MTF2 knockdown counteracts this effect, highlighting the importance of the PCIF1-MTF2 axis. Clinical analyses further reveal that high PCIF1 expression and low MTF2 expression correlate with advanced tumour stage, poor treatment response and decreased overall survival. Furthermore, in a preclinical mouse model, PCIF1 knockout enhanced the efficacy of anti-PD1 immunotherapy, reducing tumour burden and improving histological outcomes. Notably, flow cytometry analysis indicated that PCIF1 primarily exerts its effects through tumour-intrinsic mechanisms rather than direct modulation of the immune microenvironment, distinguishing its mode of action from PD1 blockade. These findings establish PCIF1 and MTF2 as promising prognostic markers and therapeutic targets for OSCC, offering new avenues for treatment strategies and patient stratification.

Keywords

m6Am modification / MTF2 / OSCC / PCIF1

References

[1] Morgan E, Soerjomataram I, Rumgay H, et al. The global landscape of esophageal squamous cell carcinoma and esophageal adenocarcinoma incidence and mortality in 2020 and projections to 2040: new estimates from GLOBOCAN 2020. Gastroenterology. 2022; 163(3): 649-658.e2.

[2] Abnet CC, Arnold M, Wei WQ. Epidemiology of esophageal squamous cell carcinoma. Gastroenterology. 2018; 154(2): 360-373.

[3] Zhou B, Bie F, Zang R, et al. Global burden and temporal trends in incidence and mortality of oesophageal cancer. J Adv Res. 2023; 50: 135-144.

[4] Shah MA, Altorki N, Patel P, Harrison S, Bass A, Abrams JA. Improving outcomes in patients with oesophageal cancer. Nat Rev Clin Oncol. 2023; 20(6): 390-407.

[5] Deboever N, Jones CM, Yamashita K, Ajani JA, Hofstetter WL. Advances in diagnosis and management of cancer of the esophagus. BMJ. 2024; 385: e074962.

[6] Kelly RJ. Emerging multimodality approaches to treat localized esophageal cancer. J Natl Compr Canc Netw. 2019; 17(8): 1009-1014.

[7] Yang H, Liu H, Chen Y, et al. Long-term efficacy of neoadjuvant chemoradiotherapy plus surgery for the treatment of locally advanced esophageal squamous cell carcinoma: the NEOCRTEC5010 randomized clinical trial. JAMA Surg. 2021; 156(8): 721-729.

[8] Lagergren J, Smyth E, Cunningham D, Lagergren P. Oesophageal cancer. Lancet. 2017; 390(10110): 2383-2396.

[9] An Y, Duan H. The role of m6A RNA methylation in cancer metabolism. Mol Cancer. 2022; 21(1): 14.

[10] Han M, Sun H, Zhou Q, et al. Effects of RNA methylation on tumor angiogenesis and cancer progression. Mol Cancer. 2023; 22(1): 198.

[11] Boulias K, Toczydlowska-Socha D, Hawley BR, et al. Identification of the m(6)Am methyltransferase PCIF1 reveals the location and functions of m(6)Am in the transcriptome. Mol Cell. 2019; 75(3): 631-643.e8.

[12] Zhuo W, Sun M, Wang K, et al. m(6)Am methyltransferase PCIF1 is essential for aggressiveness of gastric cancer cells by inhibiting TM9SF1 mRNA translation. Cell Discov. 2022; 8(1): 48.

[13] Gao S, Zhou J, Hu Z, et al. Effects of the m6Am methyltransferase PCIF1 on cell proliferation and survival in gliomas. Biochim Biophys Acta Mol Basis Dis. 2022; 1868(11): 166498.

[14] Akichika S, Hirano S, Shichino Y, et al. Cap-specific terminal N (6)-methylation of RNA by an RNA polymerase II-associated methyltransferase. Science. 2019; 363(6423): eaav0080.

[15] Sun H, Zhang M, Li K, Bai D, Yi C. Cap-specific, terminal N(6)-methylation by a mammalian m(6)Am methyltransferase. Cell Res. 2019; 29(1): 80-82.

[16] Wang L, Wu L, Zhu Z, et al. Role of PCIF1-mediated 5'-cap N6-methyladeonsine mRNA methylation in colorectal cancer and anti-PD-1 immunotherapy. EMBO J. 2023; 42(2): e111673.

[17] Li K, Chen J, Zhang C, et al. The CTBP2-PCIF1 complex regulates m6Am modification of mRNA in head and neck squamous cell carcinoma. J Clin Invest. 2023; 133(20): e170173.

[18] Chen D, Gu X, Nurzat Y, et al. Writers, readers, and erasers RNA modifications and drug resistance in cancer. Mol Cancer. 2024; 23(1): 178.

[19] Relier S, Ripoll J, Guillorit H, et al. FTO-mediated cytoplasmic m(6)A(m) demethylation adjusts stem-like properties in colorectal cancer cell. Nat Commun. 2021; 12(1): 1716.

[20] Fischer S, Liefke R. Polycomb-like proteins in gene regulation and cancer. Genes. 2023; 14(4): 938.

[21] Petracovici A, Bonasio R. Distinct PRC2 subunits regulate maintenance and establishment of Polycomb repression during differentiation. Mol Cell. 2021; 81(12): 2625-2639.

[22] Chen S, Jiao L, Liu X, Yang X, Liu X. A dimeric structural scaffold for PRC2-PCL targeting to CpG island chromatin. Mol Cell. 2020; 77(6): 1265-1278.

[23] Tamburri S, Lavarone E, Fernandez-Perez D, et al. Histone H2AK119 mono-ubiquitination is essential for Polycomb-mediated transcriptional repression. Mol Cell. 2020; 77(4): 840-856.e5.

[24] Maganti HB, Jrade H, Cafariello C, et al. Targeting the MTF2-MDM2 axis sensitizes refractory acute myeloid leukemia to chemotherapy. Cancer Discov. 2018; 8(11): 1376-1389.

[25] Long Y, Wang Y, Qu M, Zhang D, Zhang X, Zhang J. Combined inhibition of EZH2 and the autotaxin-LPA-LPA2 axis exerts synergistic antitumor effects on colon cancer cells. Cancer Lett. 2023; 566: 216226.

[26] Liu J, Dou X, Chen C, et al. N (6)-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription. Science. 2020; 367(6477): 580-586.

[27] Xu W, He C, Kaye EG, et al. Dynamic control of chromatin-associated m(6)A methylation regulates nascent RNA synthesis. Mol Cell. 2022; 82(6): 1156-1168.e7.

[28] Sendinc E, Valle-Garcia D, Dhall A, et al. PCIF1 catalyzes m6Am mRNA methylation to regulate gene expression. Mol Cell. 2019; 75(3): 620-630.

[29] Mieczkowska IK, Pantelaiou-Prokaki G, Prokakis E, et al. Decreased PRC2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatments. Cell Death Dis. 2021; 12(12): 1118.

[30] Wang Q, Chen C, Ding Q, et al. METTL3-mediated m(6)A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance. Gut. 2020; 69(7): 1193-1205.

[31] Wan W, Ao X, Chen Q, et al. METTL3/IGF2BP3 axis inhibits tumor immune surveillance by upregulating N(6)-methyladenosine modification of PD-L1 mRNA in breast cancer. Mol Cancer. 2022; 21(1): 60.

[32] Hou G, Zhao X, Li L, et al. SUMOylation of YTHDF2 promotes mRNA degradation and cancer progression by increasing its binding affinity with m6A-modified mRNAs. Nucleic Acids Res. 2021; 49(5): 2859-2877.

[33] Pan Y, Chen H, Zhang X, et al. METTL3 drives NAFLD-related hepatocellular carcinoma and is a therapeutic target for boosting immunotherapy. Cell Rep Med. 2023; 4(8): 101144.

[34] Yin H, Zhang X, Yang P, et al. RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming. Nat Commun. 2021; 12(1): 1394.

[35] Tay C, Tanaka A, Sakaguchi S. Tumor-infiltrating regulatory T cells as targets of cancer immunotherapy. Cancer Cell. 2023; 41(3): 450-465.

[36] Bao Y, Zhai J, Chen H, et al. Targeting m(6)A reader YTHDF1 augments antitumour immunity and boosts anti-PD-1 efficacy in colorectal cancer. Gut. 2023; 72(8): 1497-1509.

[37] Hu Y, Gong C, Li Z, et al. Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m6A modification. Mol Cancer. 2022; 21(1): 34.

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.