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Circadian lncRNA ADIRF-AS1 binds PBAF and regulates renal clear cell tumorigenesis

Rebekah Brooks1, Judith Monzy2, Bailey Aaron2

  • 1Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Wistar Institute, Philadelphia, PA, USA; The Ludwig Institute for Cancer Research, New York, NY, USA.

Cell Reports
|October 19, 2022
PubMed

Insights

ADIRF-AS1, a circadian long non-coding RNA (lncRNA), regulates clock and extracellular matrix genes. It functions partly through the PBAF complex and acts as an oncogenic lncRNA in clear cell renal carcinoma (ccRCC).

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Chronobiology

Background:

  • Circadian rhythms influence gene expression, including those involved in cancer.
  • Long non-coding RNAs (lncRNAs) play critical roles in gene regulation and disease.
  • The PBAF complex, involving PBRM1, is a tumor suppressor frequently mutated in clear cell renal carcinoma (ccRCC).

Purpose of the Study:

  • To identify and characterize the role of the circadian lncRNA ADIRF-AS1.
  • To investigate the functional relationship between ADIRF-AS1, the PBAF complex, and ccRCC.
  • To determine the impact of ADIRF-AS1 on ccRCC tumorigenesis and patient survival.

Main Methods:

  • Identification of ADIRF-AS1 as a circadian lncRNA.
  • Functional studies in U2OS and ccRCC cell lines involving gene deletion and knockdown.
  • Analysis of ADIRF-AS1 interaction with the PBAF complex.
  • Correlation analysis of ADIRF-AS1 expression with patient survival data.
  • In vivo tumorigenesis assays in mouse models.

Main Results:

  • ADIRF-AS1 deletion alters rhythmicity of clock-controlled and extracellular matrix genes.
  • ADIRF-AS1 interacts with all PBAF complex components and modulates PBAF-suppressed genes in ccRCC.
  • ADIRF-AS1 expression correlates with survival in ccRCC, particularly in PBRM1 wild-type tumors.
  • Loss of ADIRF-AS1 inhibits in vivo tumorigenesis, with a partially PBRM1-independent function.

Conclusions:

  • ADIRF-AS1 is a BMAL1-CLOCK-regulated, oncogenic lncRNA that partly functions through the PBAF complex.
  • ADIRF-AS1 plays a significant role in ccRCC development and progression.
  • ADIRF-AS1 represents a potential therapeutic target in ccRCC, especially in PBRM1 wild-type cases.
Keywords:
ADIRF-AS1CP: CancerPBAFccRCCcircadian rhythmclocklncRNA

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