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Loss of PBRM1 Alters Promoter Histone Modifications and Activates ALDH1A1 to Drive Renal Cell Carcinoma

David A Schoenfeld1, Royce Zhou2, Sakellarios Zairis3

  • 1Section of Medical Oncology, Yale School of Medicine, New Haven, Connecticut.

Molecular Cancer Research : MCR
|April 12, 2022
PubMed

Insights

Loss of the tumor suppressor PBRM1 in clear cell renal cell carcinoma (ccRCC) alters histone modifications and upregulates ALDH1A1, increasing tumor potential. ARID2 is crucial for this PBRM1-loss effect.

Area of Science:

  • Cancer Biology
  • Epigenetics
  • Chromatin Remodeling

Background:

  • SWI/SNF chromatin remodeling complexes regulate gene expression and are frequently altered in cancer.
  • The PBAF complex, a SWI/SNF subtype, contains unique subunits including the tumor suppressor PBRM1 (BAF180).
  • PBRM1 mutations are prevalent in clear cell renal cell carcinoma (ccRCC), suggesting a role in tumorigenesis.

Purpose of the Study:

  • To investigate the functional consequences of PBRM1 loss on the epigenome and gene expression in ccRCC.
  • To identify downstream targets and mechanisms by which PBRM1 loss contributes to ccRCC development.
  • To elucidate the role of other PBAF subunits in PBRM1-mediated regulation.

Main Methods:

  • Integration of RNA-sequencing, ChIP-sequencing (H3K4me3), and ATAC-sequencing data.
  • Analysis of ccRCC cell lines and primary tumors.
  • Biochemical assays to assess protein interactions and functional dependencies.

Main Results:

  • PBRM1 loss leads to de novo gains in H3K4me3 peaks across the epigenome.
  • Activation of a retinoic acid biosynthesis and signaling gene signature, including upregulation of ALDH1A1.
  • ALDH1A1 upregulation enhances the tumorigenic potential of ccRCC cells.
  • ARID2, but not other core SWI/SNF components like BRG1, is essential for ALDH1A1 induction upon PBRM1 loss.

Conclusions:

  • PBRM1 functions as a tumor suppressor in ccRCC by regulating histone modifications and retinoic acid signaling.
  • ALDH1A1 is a key downstream target of PBRM1 loss, contributing to ccRCC aggressiveness.
  • The PBAF subunit ARID2 plays a critical role in mediating the effects of PBRM1 loss on target gene expression.

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