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Genistein Represses HOTAIR/Chromatin Remodeling Pathways to Suppress Kidney Cancer

Mitsuho Imai-Sumida¹, Pritha Dasgupta¹, Priyanka Kulkarni¹

¹Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, USA.

Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology

|January 22, 2020

Abstract

Background/Aims:

Genistein, a soy isoflavone, has been shown to have anti-cancer effects in various cancers including renal cancer. Long non-coding RNA, HOX transcript antisense RNA (HOTAIR), is involved in cancer progression and metastasis, such as renal cancer. Our aim was to investigate the effects of genistein on HOTAIR chromatin remodeling functions.

Methods:

We used MTS assays and Transwell migration assays to study the effects of genistein on cell proliferation and migration respectively in human renal cell carcinoma (RCC) cell lines. We used Western blots to analyze SNAIL and ZO-1 expression. We performed chromatin immunoprecipitation (ChIP) assays to study recruitment of the polycomb repressive complex 2 (PRC2) to the ZO-1 promoter. We performed RNA immunoprecipitation (RIP) assays to study interaction between HOTAIR and PRC2, SMARCB1 or ARID1A. We also performed transfection experiments to overexpress EED, HOTAIR and knockdown SMARCB1.

Results:

Genistein reduced cell proliferation and migration of human renal cell carcinoma cell lines. ChIP assays indicated that genistein reduces recruitment of the PRC2 to the ZO-1 promoter and increased its expression. RIP assays showed that genistein inhibits HOTAIR interaction with PRC2, leading to tumor suppression. Immunoprecipitation also revealed that genistein reduced EED levels in PRC2, suggesting that decreased EED levels suppress HOTAIR interaction with PRC2. EED overexpression in the presence of genistein restored PRC2 interaction with HOTAIR and reduced ZO-1 transcription, suggesting genistein activates ZO-1 by inhibiting HOTAIR/PRC2 functions. RIP assays also showed that HOTAIR interacts with SMARCB1 and ARID1A, subunits of the human SWI/SNF chromatin remodeling complex and genistein reduces this interaction. Combination of HOTAIR overexpression and SMARCB1 knockdown in the presence of genistein revealed that genistein inhibits SNAIL transcription via the HOTAIR/SMARCB1 pathway.

Conclusion:

Genistein suppresses EED levels in PRC2 and inhibits HOTAIR/PRC2 interaction. Genistein suppresses HOTAIR/PRC2 recruitment to the ZO-1 promoter and enhances ZO-1 transcription. Genistein also inhibits SNAIL transcription via reducing HOTAIR/SMARCB1 interaction. We demonstrate that the reduction of HOTAIR interaction with chromatin remodeling factors by genistein represses HOTAIR/chromatin remodeling pathways to suppress RCC malignancy.

Insights

Genistein, a soy isoflavone, suppresses renal cancer progression by inhibiting the HOTAIR/PRC2 and HOTAIR/SMARCB1 pathways. This leads to reduced cell proliferation, migration, and enhanced ZO-1 expression, ultimately suppressing renal cell carcinoma malignancy.

Area of Science:

Oncology
Molecular Biology
Epigenetics

Background:

Genistein, a soy isoflavone, exhibits anti-cancer properties, particularly in renal cancer.
Long non-coding RNA HOTAIR is implicated in the progression and metastasis of renal cell carcinoma.
Investigating genistein's impact on HOTAIR's chromatin remodeling functions is crucial for understanding its anti-cancer mechanisms.

Purpose of the Study:

To investigate the effects of genistein on the chromatin remodeling functions of HOTAIR in renal cell carcinoma (RCC).
To elucidate the molecular mechanisms by which genistein suppresses RCC progression.
To determine genistein's influence on key regulatory pathways involving HOTAIR, PRC2, and SMARCB1.

Main Methods:

Utilized MTS and Transwell assays to assess genistein's effects on RCC cell proliferation and migration.
Employed Western blotting to analyze SNAIL and ZO-1 expression.
Conducted Chromatin Immunoprecipitation (ChIP) and RNA Immunoprecipitation (RIP) assays to study protein-DNA and protein-RNA interactions, respectively.
Performed transfection experiments for gene overexpression and knockdown.

Main Results:

Genistein reduced RCC cell proliferation and migration.
Genistein decreased Polycomb Repressive Complex 2 (PRC2) recruitment to the ZO-1 promoter, increasing ZO-1 expression.
Genistein inhibited the interaction between HOTAIR and PRC2 by suppressing EED levels, and also reduced HOTAIR interaction with SMARCB1, inhibiting SNAIL transcription.

Conclusions:

Genistein suppresses RCC malignancy by inhibiting HOTAIR/PRC2 and HOTAIR/SMARCB1 interactions.
Genistein enhances ZO-1 transcription by disrupting HOTAIR/PRC2 recruitment to the ZO-1 promoter.
Genistein inhibits SNAIL transcription through the reduction of HOTAIR/SMARCB1 interaction, thereby repressing oncogenic pathways.

Read full analysis

Keywords:

Genistein HOTAIR PRC2 Renal cancer SMARCB1

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