TRIP4 transcriptionally activates DDIT4 and subsequent mTOR signaling to promote glioma progression

• Published in: Free radical biology & medicine 2021-12, Vol.177, p.31-47
• Main Authors: Li, Wenyang, Hu, Sheng, Tian, Chunfang, Wan, Xinyu, Yu, Wendan, Guo, Ping, Zhao, Feng, Hua, Chunyu, Lu, Xiaona, Xue, Guoqing, Han, Shilong, Guo, Wei, Wang, Dong, Deng, Wuguo
• Format: Article
• Language: English
• Subjects: Apoptosis; Cell Line, Tumor; Cell Proliferation; DDIT4; Gene Expression Regulation, Neoplastic; Glioma; Glioma - genetics; Humans; mTOR; Signal Transduction; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transcription Factors; TRIP4
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2021.10.009

In spite of significant advances in the understanding of glioma biology and pathology, survival remains poor. Therefore, it is still of great significance to further explore the key factors involved in tumorigenesis and development in glioma and find potential new therapeutic targets. Here, we show that thyroid hormone receptor interactor 4 (TRIP4) is highly expressed in glioma cells and tissues. Patients of glioma with high expression of TRIP4 possess poor overall survival. Knockdown of TRIP4 inhibited tumor cell proliferation, metastasis, and apoptosis suppression, whereas overexpression of TRIP4 displays the opposite effects. Further research showed that TRIP4 promoted glioma progression through regulating DDIT4 expression and subsequent activation of mTOR signaling. DDIT4 overexpression restored the inhibition of tumor growth by TRIP4 knockdown in vitro and in vivo. Consistently, mTOR activity inhibition reversed TRIP4 overexpression-mediated tumor promotion in vitro and in vivo. Moreover, molecular mechanism exploration demonstrates that TRIP4 functions as a specific transcriptional activator to anchor at the promoter region of DDIT4 gene (−196 to −11) to regulate its transcription and such regulation was affected by HIF1α. Clinically, TRIP4 expression is positively correlated with DDIT4 expression in glioma samples based on tissue microarray analysis and both of their high expression predicts the malignancy of the disease. Altogether, our findings identify TRIP4 as a critical promoter of glioma progression by targeting DDIT4 and mTOR signaling successively and suggest that TRIP4-DDIT4 axis has potential to be a novel therapeutic target in glioma treatment. [Display omitted] •TRIP4 was highly expressed in glioma cells and tissues and patients of glioma with high expression of TRIP4 possess poor overall survival.•TRIP4 knockdown effectively led to the inhibited proliferative capacity, invasive ability and the enhanced apoptosis induction in glioma cells.•TRIP4 transcriptionally regulated DDIT4 via anchoring at its promoter region and further activated mTOR signaling in glioma cells.•DDIT4 overexpression or mTOR inhibition reversed TRIP4 knockdown or overexpression-mediated tumor delay or promotion in vitro and in vivo.•TRIP4 expression is positively correlated with DDIT4 expression in glioma samples and their high expression predicts the severity of glioma.