The CTBP2-PCIF1 complex regulates m6Am modification of mRNA in head and neck squamous cell carcinoma
Kang Li, … , Qianming Chen, Demeng Chen
Kang Li, … , Qianming Chen, Demeng Chen
Published August 29, 2023
Citation Information: J Clin Invest. 2023;133(20):e170173. https://doi.org/10.1172/JCI170173.
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Research Article Cell biology Oncology

The CTBP2-PCIF1 complex regulates m6Am modification of mRNA in head and neck squamous cell carcinoma

Abstract

PCIF1 can mediate the methylation of N6,2′-O-dimethyladenosine (m6Am) in mRNA. Yet, the detailed interplay between PCIF1 and the potential cofactors and its pathological significance remain elusive. Here, we demonstrated that PCIF1-mediated cap mRNA m6Am modification promoted head and neck squamous cell carcinoma progression both in vitro and in vivo. CTBP2 was identified as a cofactor of PCIF1 to catalyze m6Am deposition on mRNA. CLIP-Seq data demonstrated that CTBP2 bound to similar mRNAs as compared with PCIF1. We then used the m6Am-Seq method to profile the mRNA m6Am site at single-base resolution and found that mRNA of TET2, a well-known tumor suppressor, was a major target substrate of the PCIF1-CTBP2 complex. Mechanistically, knockout of CTBP2 reduced PCIF1 occupancy on TET2 mRNA, and the PCIF1-CTBP2 complex negatively regulated the translation of TET2 mRNA. Collectively, our study demonstrates the oncogenic function of the epitranscriptome regulator PCIF1-CTBP2 complex, highlighting the importance of the m6Am modification in tumor progression.

Authors

Kang Li, Jie Chen, Caihua Zhang, Maosheng Cheng, Shuang Chen, Wei Song, Chunlong Yang, Rongsong Ling, Zhi Chen, Xiaochen Wang, Gan Xiong, Jieyi Ma, Yan Zhu, Quan Yuan, Qi Liu, Liang Peng, Qianming Chen, Demeng Chen

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Figure 7

Conditional knockout of CTBP2 inhibits tumor growth and metastasis in vivo via enhanced expression of TET2.

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Conditional knockout of CTBP2 inhibits tumor growth and metastasis in vi...
(A) Experimental design of the carcinogen-induced HNSCC mouse model. (B) Diagram of Cre-dependent conditional knockout strategy for Ctbp2. (C) Representative image of visible tongue lesions in the indicated groups. Scale bar: 1 mm. (D) Quantification of HNSCC lesion area in the indicated groups (n = 8). *P < 0.05, ***P < 0.001 by 1-way ANOVA with Tukey’s multiple-comparison test. (E) Representative H&E staining of HNSCC in the indicated groups. Scale bar: 100 μm. (F) Quantification of HNSCC number of lesions in the indicated groups (n = 8). *P < 0.05, ***P < 0.001 by 1-way ANOVA with Tukey’s multiple-comparison test. (G) Quantification of HNSCC tumor grade in the indicated groups. *P < 0.05 by Pearson’s χ2 test. (H) Representative PCK staining of metastatic lymph node in the indicated groups. Scale bar: 300 μm. (I) Quantification of metastatic lymph node percentage in the indicated groups. *P < 0.05 by Pearson’s χ2 test. (J–L) Representative dot blot image (J) and quantitative analysis of DNA 5mC (K) and 5hmC (L) modification levels in the indicated groups (n = 3). **P < 0.01, ***P < 0.001 by 1-way ANOVA with Tukey’s multiple-comparison test.