N6-methyladenosine enhances the expression of TGF-β-SMAD signaling family to inhibit cell growth and promote cell metastasis

Bo Peng; Shuwen Cheng; He Wang; Tongfeng Liu; Yinmin Gu; Liqiang Duan; Tianyou Cheng; Xuetong Wang; Xiaodong Wang; Qingqing Zhang; Yibi Zhang; Xueqing Zhao; Xijuan Yao; Xujie Zhao; Dalong Song; Jian Zeng; Shan Gao

doi:10.1016/j.canlet.2024.217195

N⁶-methyladenosine enhances the expression of TGF-β-SMAD signaling family to inhibit cell growth and promote cell metastasis

Cancer Lett. 2024 Oct 28:603:217195. doi: 10.1016/j.canlet.2024.217195. Epub 2024 Aug 31.

Authors

Bo Peng¹, Shuwen Cheng², He Wang³, Tongfeng Liu⁴, Yinmin Gu⁵, Liqiang Duan⁶, Tianyou Cheng⁶, Xuetong Wang¹, Xiaodong Wang¹, Qingqing Zhang⁵, Yibi Zhang¹, Xueqing Zhao⁵, Xijuan Yao⁵, Xujie Zhao⁵, Dalong Song⁷, Jian Zeng⁸, Shan Gao⁹

Affiliations

¹ School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230000, China; Chinese Academy of Sciences (CAS) Key Laboratory of Biomedical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, 215163, China; Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China.
² Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China; Medical School of Nanjing University, Nanjing, 210046, China.
³ Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China; Department of Chemistry, College of Sciences, Shanghai University, Shangha, 200444, China.
⁴ Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China; Medical College, Guizhou University, Guiyang, 550025, China.
⁵ Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China.
⁶ Shanxi Academy of Advanced Research and Innovation, Shanxi Provincial Key Laboratory of Protein Structure Determination, Taiyuan, 030032, China.
⁷ Department of Urology, Guizhou Provincial People's Hospital, Guiyang, China. Electronic address: [email protected].
⁸ Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Department of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China; Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
⁹ Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China. Electronic address: [email protected].

PMID: 39222678
DOI: 10.1016/j.canlet.2024.217195

Abstract

TGF-β-SMAD signaling pathway plays an important role in the progression of various cancers. However, posttranscriptional regulation such as N⁶-methyladenosine (m⁶A) of TGF-β-SMAD signaling axis remains incompletely understood. Here, we reveal that insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) is low expression as well as associated with poor prognosis in clear cell renal cell carcinoma (ccRCC) patients and inhibits proliferation as well as promotes metastasis of ccRCC cells. Mechanistically, IGF2BP2 systematically regulates TGF-β-SMAD signaling family, including TGF-β1/2, TGF-βR1/2 and SMAD2/3/4, through mediating their mRNA stability in an m⁶A-dependent manner. Furthermore, the functional effects of IGF2BP2 on ccRCC cells is mediated by TGF-β-SMAD signaling downstream effector SMAD4, which is identified three m⁶A sites in 5'UTR and CDS. Our study establishes IGF2BP2-TGF-β-SMAD axis as a new regulatory effector in ccRCC, providing new insights for developing novel therapeutic strategies.

Keywords: IGF2BP2; SMAD; TGF-β; ccRCC; m(6)A.

MeSH terms

Adenosine* / analogs & derivatives
Adenosine* / metabolism
Animals
Carcinoma, Renal Cell* / genetics
Carcinoma, Renal Cell* / metabolism
Carcinoma, Renal Cell* / pathology
Cell Line, Tumor
Cell Movement
Cell Proliferation*
Gene Expression Regulation, Neoplastic*
Humans
Kidney Neoplasms* / genetics
Kidney Neoplasms* / metabolism
Kidney Neoplasms* / pathology
Mice
Neoplasm Metastasis
RNA Stability
RNA-Binding Proteins* / genetics
RNA-Binding Proteins* / metabolism
Signal Transduction*
Smad Proteins* / genetics
Smad Proteins* / metabolism
Smad4 Protein / genetics
Smad4 Protein / metabolism
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism

Substances

N-methyladenosine
Adenosine
RNA-Binding Proteins
Smad Proteins
IGF2BP2 protein, human
Transforming Growth Factor beta
SMAD4 protein, human
Smad4 Protein