Supplementary Figure S2 from THG-1/TSC22D4 Promotes IL-1 Signaling through Stabilization of TRAF6 in Squamous Cell Carcinoma

Okano, Yasuhito; Suzuki, Hiroyuki; Watanabe, Yukihide; Abdelaziz, Mohammed; Manevich, Lev; Kawanishi, Kunio; Ozaki, Haruka; Ishii, Ryota; Matsumoto, Shin; Goto, Nohara; Zheng, Ling; Okita, Yukari; Hwang, Jongchan; Nakayama, Masahiro; Shima, Yoshihide; Sakamoto, Noriaki; Noguchi, Masayuki; Tabuchi, Keiji; Kato, Mitsuyasu

doi:10.1158/1541-7786.28917988

Supplementary Figure S2 from THG-1/TSC22D4 Promotes IL-1 Signaling through Stabilization of TRAF6 in Squamous Cell Carcinoma

journal contribution

posted on 2025-05-02, 07:22 authored by Yasuhito Okano, Hiroyuki Suzuki, Yukihide Watanabe, Mohammed Abdelaziz, Lev Manevich, Kunio Kawanishi, Haruka Ozaki, Ryota Ishii, Shin Matsumoto, Nohara Goto, Ling Zheng, Yukari Okita, Jongchan Hwang, Masahiro Nakayama, Yoshihide Shima, Noriaki Sakamoto, Masayuki Noguchi, Keiji Tabuchi, Mitsuyasu Kato

Secretion of IL-1β in SCC cells.

Funding

Japan Society for the Promotion of Science (JSPS)

Japan Agency for Medical Research and Development (AMED)

History

ARTICLE ABSTRACT

Malignant neoplasms arise within a region of chronic inflammation, which is a key factor in all aspects of tumorigenesis including initiation, proliferation, invasion, angiogenesis, and metastasis. IL-1 plays critical functions in tumor development by influencing the tumor microenvironment and promoting cancer progression. However, the mechanism of continuous activation of the IL-1–mediated inflammatory pathway in tumors has not been fully elucidated. This study provides a novel mechanism of the autocrine activation of IL-1 signaling in squamous cell carcinoma (SCC) through a novel oncoprotein, TSC-22 homologous gene-1 (THG-1, also known as TSC22D4). The RNA sequencing analysis revealed that THG-1 overexpression enhances the transcription of NF-κB targets including IL1A, IL1B, TNFA, and IL8. Furthermore, THG-1 knockdown reduced the responsiveness to IL-1 through the suppression of NF-κB nuclear translocation. To elucidate the mechanism, we focused on a THG-1 interacting protein, NRBP1. We found that NRBP1 facilitates the degradation of TNF receptor–associated factor 6 (TRAF6) through its E3 ubiquitin ligase activity. THG-1 bound to NRBP1 and suppressed the degradation of TRAF6. Furthermore, THG-1 knockdown reduced TRAF6 abundance and NF-κB activity in SCC cells. Public database analyses of head and neck SCC revealed that high expression of THG-1 is associated with the activation of the IL-1 and TNF pathways, which share TRAF6 in the signal transductions. Finally, THG-1 abundance in laryngeal SCC specimens is elevated in patients with recurrence. These results indicated that THG-1 drives the self-sufficiency of IL-1–mediated inflammatory pathway, which could contribute to the future diagnosis and immunotherapy of SCCs.Implications: An oncoprotein, THG-1/TSC22D4 activates the IL-1–mediated inflammatory pathway through the suppression of TRAF6 degradation, which mediates the continuous inflammation in tumors.