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LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway

Jun Lu1,2, Liang-Min Fu1, Yun Cao3

  • 1Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.

Oncogene
|March 25, 2023
PubMed

Insights

Leucine zipper and sterile alpha motif containing transcription factor 1 (LZTFL1) suppresses clear cell renal cell carcinoma (ccRCC) growth by targeting AKT. Restoring LZTFL1 may offer a new therapeutic strategy for kidney cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Leucine zipper and sterile alpha motif containing transcription factor 1 (LZTFL1) is located at chromosomal region 3p21.3, a site frequently deleted in various cancers.
  • The specific role of LZTFL1 in kidney tumorigenesis, particularly clear cell renal cell carcinoma (ccRCC), has remained largely unknown.
  • Frequent and early deletion of LZTFL1 suggests a potential tumor suppressive function in cancer development.

Purpose of the Study:

  • To investigate the hypothesized tumor suppressive function of LZTFL1 in clear cell renal cell carcinoma (ccRCC).
  • To elucidate the underlying mechanism of LZTFL1's action in kidney cancer.
  • To evaluate the potential of LZTFL1 as a prognostic marker and therapeutic target in ccRCC.

Main Methods:

  • Extensive bioinformatics analysis of patient tumor data.
  • Gain- and loss-of-function studies in kidney tumor cell lines.
  • Validation using patient-derived xenograft (PDX) model systems.
  • Assessment of LZTFL1 expression, AKT destabilization, and cell cycle progression.

Main Results:

  • LZTFL1 inhibits ccRCC cell proliferation by destabilizing AKT via the ZNRF1-mediated ubiquitin-proteasome pathway.
  • LZTFL1 induces cell cycle arrest at the G1 phase in kidney tumor cells.
  • LZTFL1 is frequently deleted in ccRCC, and its downregulation correlates with poor patient outcomes.
  • Overexpression of LZTFL1 in PDX models suppressed tumor growth.

Conclusions:

  • LZTFL1 exhibits a tumor suppressive role in clear cell renal cell carcinoma.
  • LZTFL1 downregulation is associated with adverse ccRCC prognosis, suggesting its utility as a prognostic marker.
  • Restoring LZTFL1 expression represents a potential therapeutic strategy for ccRCC.

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