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
  • 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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