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Yang, Tony J.H.

University of British Columbia

Epigenetic alterations resulting in a dysregulated transcriptional program of the cell have been previously described in liver cancer. Importantly, certain fruits including grapes and berries contain stilbenoid polyphenols, such as pterostilbene (PTS) and resveratrol (RSV), that have been shown to reverse epigenetic alterations by remodeling DNA methylation patterns. However, the underlying downstream mechanisms of the anticancer actions of PTS and RSV remain unclear. Here, we describe a novel cancer-promoting gene, BRUNOL5, in the hepatocellular carcinoma (HCC) cell line, HepG2, is regulated by PTS/RSV. Using siRNA-mediated knockdown of BRUNOL5 followed by RNA sequencing, we determined 4,406 transcripts with significantly dysregulated expression profiles in response to depletion of BRUNOL5. Many genes with significant downregulation were found to have oncogenic functions, whereas genes with significant upregulation were found to have tumour-suppressive functions. We selected multiple downregulated candidates including TLR4, TIMP3, and MMP2 for further investigation, considering their functions that promote cell proliferation and invasion, migration, and metastasis. Additionally, we observed significant downregulation of genes involved in various oncogenic signaling pathways including Notch, Wnt, TGFB/BMP, and Hhg signaling. We then investigated various candidate upregulated transcripts, including MST1, SLC22A7, and CDHR5, that are involved in promoting apoptosis, increasing chemosensitivity and cell adhesion. Interestingly, depletion of BRUNOL5 mimicked the effects of PTS/RSV treatment of HepG2 cells. PTS/RSV treatment of HepG2 correlated with significant BRUNOL5 promoter hypermethylation, which corresponded with significant decreases of BRUNOL5 at both transcript and protein levels. Interestingly, we observed similar effects of PTS/RSV on the aforementioned oncogenic signaling pathways. Our findings indicate that BRUNOL5 is a novel cancer-promoting gene regulated by stilbenoid polyphenols, and that the pleiotropic anti-cancer effects of PTS/RSV may possibly be mediated, at least partially, through BRUNOL5 epigenetic downregulation. Through RNA immunoprecipitation followed by qPCR, we discovered decreased BRUNOL5 binding to TLR4 and CYR61 transcripts, potentially connecting with a decrease in the level of those transcripts. Our findings describe a novel cancer-promoting gene in HCC that is epigenetically regulated by stilbenoids. We further provide a better understanding of a potential mechanism that may contribute to the anti-cancer action of stilbenoid polyphenols.

Text

2024-04-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/84339

Human Nutrition

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/