Chrysin-Induced Regression of Angiogenesis via an Induction of DNA Damage Response and Oxidative Stress in In Vitro and In Vivo Models of Melanoma

Despite the progress made in treatments, melanoma is one of the cancers for which its incidence and mortality have increased during recent decades. In the research of new therapeutic strategies, natural polyphenols such as chrysin could be good candidates owing to their capacities to modulate the different fundamental aspects of tumorigenesis and resistance mechanisms, such as oxidative stress and neoangiogenesis. In the present study, we sought to determine whether chrysin could exert antitumoral effects via the modulation of angiogenesis by acting on oxidative stress and associated DNA damage. For the first time, we show a link between chrysin-induced antiproliferative effects, the activation of the DNA damage pathway, and its ability to limit angiogenesis. More specifically, herein, we show that chrysin induces single- and double-stranded DNA breaks via the activation of the DNA damage response pathway: ATM (ataxia-telangiectasia-mutated)/Chk2 (checkpoint kinase 2) and ATR (ataxia telangiectasia and Rad3-related)/Chk1 (checkpoint kinase 1) pathways. Strong activation of this DNA damage response was found to be partly involved in the ability of chrysin to limit angiogenesis and may partly involve a direct interaction between the polyphenol and DNA G-quadruplex structures responsible for the replication fork collapse. Moreover, these events were associated with a marked reduction in melanoma cells’ capacity to secrete proangiogenic factor VEGF-A. The disruption of these key protein actors in tumor growth by chrysin was also confirmed in a syngeneic model of B16 melanoma. This last point is of importance to further consider the use of chrysin as a new therapeutic strategy in melanoma treatment

The ubiquitin-like modifier FAT10 is induced in MASLD and impairs the lipid-regulatory activity of PPAR\u3b1

Abstract: Background and aims: Peroxisome Proliferator-Activated Receptor alpha (PPAR alpha) is a key regulator of hepatic lipid metabolism and therefore a promising therapeutic target against Metabolic-dysfunction Associated Steatotic Liver Diseases (MASLD). However, its expression and activity decrease during disease progression and several of its agonists did not achieve sufficient efficiency in clinical trials with, surprisingly, a lack of steatosis improvement. Here, we identified the Human leukocyte antigen-F Adjacent Transcript 10 (FAT10) as an inhibitor of PPAR alpha lipid metabolic activity during MASLD progression.Approach and results: In vivo, the expression of FAT10 is upregulated in human and murine MASLD livers upon disease progression and correlates negatively with PPAR alpha expression. The increase of FAT10 occurs in hepatocytes in which both proteins interact. FAT10 silencing in vitro in hepatocytes increases PPAR alpha target gene expression, promotes fatty acid oxidation and decreases intra-cellular lipid droplet content. In line, FAT10 overexpression in hepatocytes in vivo inhibits the lipid regulatory activity of PPAR alpha in response to fasting and agonist treatment in conditions of physiological and pathological hepatic lipid overload.Conclusions: FAT10 is induced during MASLD development and interacts with PPAR alpha resulting in a decreased lipid metabolic response of PPAR alpha to fasting or agonist treatment. Inhibition of the FAT10-PPAR alpha interaction may provide a means to design potential therapeutic strategies against MASLD