PRDM16 suppresses HIF-targeted gene expression in kidney cancer
Anirban Kundu1, Hyeyoung Nam1, Sandeep Shelar1
1Department of Urology, University of Alabama at Birmingham, Birmingham, AL.
Abstract:
Analysis of transcriptomic data demonstrates extensive epigenetic gene silencing of the transcription factor PRDM16 in renal cancer. We show that restoration of PRDM16 in RCC cells suppresses in vivo tumor growth. RNaseq analysis reveals that PRDM16 imparts a predominantly repressive effect on the RCC transcriptome including suppression of the gene encoding semaphorin 5B (SEMA5B). SEMA5B is a HIF target gene highly expressed in RCC that promotes in vivo tumor growth. Functional studies demonstrate that PRDM16's repressive properties, mediated by physical interaction with the transcriptional corepressors C-terminal binding proteins (CtBP1/2), are required for suppression of both SEMA5B expression and in vivo tumor growth. Finally, we show that reconstitution of RCC cells with a PRDM16 mutant unable to bind CtBPs nullifies PRDM16's effects on both SEMA5B repression and tumor growth suppression. Collectively, our data uncover a novel epigenetic basis by which HIF target gene expression is amplified in kidney cancer and a new mechanism by which PRDM16 exerts its tumor suppressive effects.
Insights
Restoring PRDM16 in kidney cancer cells halts tumor growth by epigenetically silencing genes like SEMA5B. This involves PRDM16 interacting with corepressors, revealing a new tumor suppressor mechanism.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Renal cell carcinoma (RCC) exhibits extensive epigenetic gene silencing of the transcription factor PRDM16.
- PRDM16 plays a crucial role in cellular differentiation and tumor suppression.
- Semaphorin 5B (SEMA5B), a hypoxia-inducible factor (HIF) target gene, is highly expressed in RCC and promotes tumor growth.
Purpose of the Study:
- To investigate the role of PRDM16 in epigenetic regulation within renal cancer.
- To elucidate the mechanism by which PRDM16 suppresses tumor growth in RCC.
- To identify novel therapeutic targets for kidney cancer treatment.
Main Methods:
- Transcriptomic analysis (RNA-seq) to assess gene expression changes.
- In vivo studies using RCC cells to evaluate tumor growth suppression.
- Co-immunoprecipitation assays to determine protein-protein interactions.
- Functional studies with PRDM16 mutants to assess the role of corepressor binding.
Main Results:
- Restoration of PRDM16 in RCC cells significantly suppressed in vivo tumor growth.
- PRDM16 exhibited a predominantly repressive effect on the RCC transcriptome, including the suppression of SEMA5B.
- PRDM16's tumor suppressive function and SEMA5B repression were dependent on its physical interaction with C-terminal binding proteins (CtBP1/2).
- A PRDM16 mutant unable to bind CtBPs failed to suppress SEMA5B expression and tumor growth.
Conclusions:
- PRDM16 acts as a tumor suppressor in renal cancer through epigenetic mechanisms.
- PRDM16 represses HIF target genes, such as SEMA5B, by interacting with CtBP corepressors.
- This study uncovers a novel epigenetic mechanism driving gene amplification in kidney cancer and highlights PRDM16 as a potential therapeutic target.
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