TSPYL1 as a Critical Regulator of TGFβ Signaling through Repression of TGFBR1 and TSPYL2

• Published in: Advanced science Vol. 11; no. 21; pp. e2306486 - n/a
• Main Authors: Tan, Huiqi, Miao, Mia Xinfang, Luo, Rylee Xu, So, Joan, Peng, Lei, Zhu, Xiaoxuan, Leung, Eva Hin Wa, Zhu, Lina, Chan, Kui Ming, Cheung, Martin, Chan, Siu Yuen
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.06.2024; John Wiley and Sons Inc; Wiley
• Subjects: Cancer; Cell growth; Cell Line, Tumor; Cloning; Epithelial-Mesenchymal Transition - genetics; FOXA1; Genes; Genotype & phenotype; Homeostasis; Humans; Kinases; Ligands; Neuroblastoma; nucleosome assembly protein; Phosphorylation; Proteins; Receptor, Transforming Growth Factor-beta Type I - genetics; Receptor, Transforming Growth Factor-beta Type I - metabolism; Signal Transduction - genetics; Student's t-test; TGFBR1; TGFβ signaling; Transcription factors; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; TSPYL1; TSPYL2; FOXA1; TSPYL2; nucleosome assembly protein; TSPYL1; TGFβ signaling; TGFBR1
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202306486

Nucleosome assembly proteins (NAPs) have been identified as histone chaperons. Testis‐Specific Protein, Y‐Encoded‐Like (TSPYL) is a newly arisen NAP family in mammals. TSPYL2 can be transcriptionally induced by DNA damage and TGFβ causing proliferation arrest. TSPYL1, another TSPYL family member, has been poorly characterized and is the only TSPYL family member known to be causal of a lethal recessive disease in humans. This study shows that TSPYL1 and TSPYL2 play an opposite role in TGFβ signaling. TSPYL1 partners with the transcription factor FOXA1 and histone methyltransferase EZH2, and at the same time represses TGFBR1 and epithelial‐mesenchymal transition (EMT). Depletion of TSPYL1 increases TGFBR1 expression, upregulates TGFβ signaling, and elevates the protein stability of TSPYL2. Intriguingly, TSPYL2 forms part of the SMAD2/3/4 signal transduction complex upon stimulation by TGFβ to execute the transcriptional responses. Depletion of TSPYL2 rescues the EMT phenotype of TSPYL1 knockdown in A549 lung carcinoma cells. The data demonstrates the prime role of TSPYL2 in causing the dramatic defects in TSPYL1 deficiency. An intricate counter‐balancing role of TSPYL1 and TSPYL2 in regulating TGFβ signaling is also unraveled. TSPYL1 partners with FOXA1 and EZH2 to repress TGFBR1 transcription, thereby mitigating the level of TGFβ receptors and sensitivity to TGFβ. TSPYL1 deficiency enhances the response to TGFβ and stabilizes the related protein TSPYL2. TSPYL2 interacts with the SMAD2/3/4 complex to regulate transcription and hence executes the context‐dependent TGFβ driven events including epithelial mesenchymal transition in BE(2)‐C and A549 cells.