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

Free Radic Biol Med. 2021 Dec;177:31-47. doi: 10.1016/j.freeradbiomed.2021.10.009. Epub 2021 Oct 11.

Abstract

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.

Keywords: DDIT4; Glioma; TRIP4; mTOR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Glioma* / genetics
  • Humans
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors

Substances

  • DDIT4 protein, human
  • TRIP4 protein, human
  • Transcription Factors
  • MTOR protein, human
  • TOR Serine-Threonine Kinases