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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Nuclear DLC1 exerts oncogenic function through association with FOXK1 for cooperative activation of MMP9 expression

Xintao Yang1,2, Feng Hu1,2, Jessica Aijia Liu3

  • 1Shenzhen Institute of Research and Innovation (HKU-SIRI), The University of Hong Kong, Shenzhen, China.

Oncogene
|March 28, 2020
PubMed

Insights

Deleted in liver cancer 1 (DLC1) acts as an oncogene in melanoma, promoting tumor growth and metastasis. Nuclear DLC1, with FOXK1, drives melanoma progression by regulating MMP9 expression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The role of Rho GTPase-activating protein (RhoGAP) deleted in liver cancer 1 (DLC1) in melanoma is unclear, with known tumor suppressor functions in other cancers.
  • DLC1's dual localization (nuclear and cytoplasmic) suggests complex roles.
  • Investigating DLC1's function in melanoma is crucial for understanding melanoma pathogenesis.

Purpose of the Study:

  • To clarify whether DLC1 acts as a tumor suppressor or oncogene in melanoma.
  • To elucidate the mechanism by which DLC1 influences melanoma growth and metastasis.
  • To identify DLC1-interacting proteins and downstream targets involved in melanoma progression.

Main Methods:

  • Analysis of DLC1 expression in melanoma tissues.
  • Functional studies assessing DLC1's role in melanoma cell growth and metastasis.
  • Mass spectrometry to identify DLC1-associated proteins.
  • RNA-sequencing to profile gene expression changes.
  • Chromatin immunoprecipitation and reporter assays to study gene regulation.

Main Results:

  • High DLC1 expression was observed in most melanoma tissues, localized in both nucleus and cytoplasm.
  • DLC1 was essential and sufficient for melanoma growth and metastasis, mediated by nuclear localization independently of its RhoGAP activity.
  • The transcription factor FOXK1 was identified as a DLC1-associated protein, facilitating nuclear translocation of DLC1.
  • DLC1 and FOXK1 cooperatively activated MMP9 expression by regulating its promoter, promoting melanoma invasion and metastasis.
  • DLC1 and FOXK1 expression levels were highly correlated in melanoma patients and cell lines.

Conclusions:

  • Nuclear DLC1 functions as an oncogene in melanoma, promoting tumor growth and metastasis.
  • The DLC1-FOXK1 complex plays a critical role in regulating MMP9 expression, driving melanoma invasion and metastasis.
  • RhoGAP proteins can have unexpected roles in transcriptional regulation, expanding their known functions.

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