2. Academic Validation
  3. Epigenetic Silencing of BMP6 by the SIN3A-HDAC1/2 Repressor Complex Drives Melanoma Metastasis via FAM83G/PAWS1

Epigenetic Silencing of BMP6 by the SIN3A-HDAC1/2 Repressor Complex Drives Melanoma Metastasis via FAM83G/PAWS1

  • Mol Cancer Res. 2022 Feb;20(2):217-230. doi: 10.1158/1541-7786.MCR-21-0289.
Dongkook Min 1,  Jaemin Byun 1,  Eun-Joon Lee 1,  Abdul A Khan 1,  Christina Liu 1,  Oliver Loudig 1 2 3,  Wei Hu 4,  Yong Zhao 1 2,  Meenhard Herlyn 5,  Benjamin Tycko 1 2 3,  Phillip A Cole 6,  Byungwoo Ryu 7 2 3
Affiliations

Affiliations

  • 1 Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, New Jersey.
  • 2 John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.
  • 3 Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
  • 4 Department of Chemistry and Chemistry Biology, Stevens Institute of Technology, Hoboken, New Jersey.
  • 5 Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, Pennsylvania.
  • 6 Division of Genetics, Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.
  • 7 Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, New Jersey. [email protected].
PMID: 34610961 DOI: 10.1158/1541-7786.MCR-21-0289
Abstract

Aberrant epigenetic transcriptional regulation is linked to metastasis, a primary cause of cancer-related death. Dissecting the epigenetic mechanisms controlling metastatic progression may uncover important insights to tumor biology and potential therapeutic targets. Here, we investigated the role of the SIN3A histone deacetylase 1 and 2 (SIN3A-HDAC1/2) complex in Cancer metastasis. Using a mouse model of melanoma metastasis, we found that the SIN3A-HDAC1/2 transcription repressor complex silences BMP6 expression, causing increased metastatic dissemination and tumor growth via suppression of BMP6-activated SMAD5 signaling. We further discovered that FAM83G/PAWS1, a downstream effector of BMP6-SMAD5 signaling, contributes critically to metastatic progression by promoting actin-dependent cytoskeletal dynamics and cell migration. Pharmacologic inhibition of the SIN3A-HDAC1/2 complex reduced the numbers of melanoma cells in the circulation and inhibited metastatic tumor growth by inducing disseminated cell dormancy, highlighting the SIN3A-HDAC1/2 repressor complex as a potential therapeutic target for blocking Cancer metastasis. IMPLICATIONS: This study identifies the novel molecular links in the metastatic progression to target cytoskeletal dynamics in melanoma and identifies the SIN3A-HDAC1/2 complex and FAM83G/PAWS1 as potential targets for melanoma adjuvant therapy.

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