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DLC1 SAM domain-binding peptides inhibit cancer cell growth and migration by inactivating RhoA

Rakesh Joshi1, Lyugao Qin2, Xuan Cao3

  • 1Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, Canada; Departments of Surgery, Pathology and Oncology, Western University, London, Ontario N6A 5A5, Canada.

The Journal of Biological Chemistry
|December 7, 2019
PubMed

Insights

Deleted-in-liver cancer 1 (DLC1) is a tumor suppressor. Researchers found that specific peptides targeting the DLC1 SAM domain can activate its tumor-suppressing RhoGAP function, inhibiting cancer cell growth and migration.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Deleted-in-liver cancer 1 (DLC1) is a tumor suppressor protein functioning via its Rho-GTPase-activating protein (RhoGAP) domain.
  • DLC1's RhoGAP activity is inhibited by intramolecular interaction with its sterile alpha motif (SAM) domain.
  • Tensin-3 (TNS3) and PTEN were previously identified as regulators that alleviate DLC1 autoinhibition.

Purpose of the Study:

  • To elucidate the molecular mechanism of TNS3/PTEN-mediated DLC1 activation.
  • To investigate the role of the DLC1 SAM domain in regulating RhoGAP activity.
  • To develop peptide-based therapeutics targeting DLC1 for cancer treatment.

Main Methods:

  • Investigated interactions between DLC1 SAM domain and TNS3/PTEN C2 domains using peptide mapping.
  • Synthesized peptides mimicking TNS3 C2 domain binding motifs and fused them to a protein transduction sequence (tat).
  • Assessed the effect of C2 peptides on DLC1 RhoGAP activity, RhoA activation, and cancer cell behavior (growth, migration).
  • Developed and tested a cyclic TNS3 C2 peptide for cellular uptake and anti-migratory effects in breast cancer cells.

Main Results:

  • DLC1 SAM domain binds to specific peptide motifs within TNS3/PTEN C2 domains.
  • C2 domain-derived peptides effectively blocked C2-SAM interaction and potently activated DLC1 RhoGAP function.
  • Peptide treatment reduced RhoA activation, inhibited soft agar colony formation, and decreased growth factor-induced cell migration.
  • A cyclic C2 peptide demonstrated efficient cellular entry and significant inhibition of MDA-MB-231 breast cancer cell migration.

Conclusions:

  • The DLC1 SAM domain acts as a peptide-binding module, mediating interactions with TNS3 and PTEN.
  • C2 domain-derived peptides can allosterically activate DLC1's tumor-suppressive RhoGAP activity.
  • DLC1 SAM domain-binding peptides represent a promising novel therapeutic strategy for cancer treatment.
Keywords:
C2 domainRas homolog gene family, member A (RhoA)RhoGAPSAM domainbreast cancercell migrationcell proliferationdeleted in liver cancer 1 (DLC1)

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