Inhibition of p300 lysine acetyltransferase activity by luteolin reduces tumor growth in head and neck squamous cell carcinoma (HNSCC) xenograft mouse model

Abstract

Chromatin acetylation is attributed with distinct functional relevance with respect to gene expression in normal and diseased conditions thereby leading to a topical interest in the concept of epigenetic modulators and therapy. We report here the identification and characterization of the acetylation inhibitory potential of an important dietary flavonoid, luteolin. Luteolin was found to inhibit p300 acetyltransferase with competitive binding to the acetyl CoA binding site. Luteolin treatment in a xenografted tumor model of head and neck squamous cell carcinoma (HNSCC), led to a dramatic reduction in tumor growth within 4 weeks corresponding to a decrease in histone acetylation. Cells treated with luteolin exhibit cell cycle arrest and decreased cell migration. Luteolin treatment led to an alteration in gene expression and miRNA profile including up-regulation of p53 induced miR-195/215, let7C; potentially translating into a tumor suppressor function. It also led to down-regulation of oncomiRNAs such as miR-135a, thereby reflecting global changes in the microRNA network. Furthermore, a direct correlation between the inhibition of histone acetylation and gene expression was established using chromatin immunoprecipitation on promoters of differentially expressed genes. A network of dysregulated genes and miRNAs was mapped along with the gene ontology categories, and the effects of luteolin were observed to be potentially at multiple levels: at the level of gene expression, miRNA expression and miRNA processing.

Identification of the SOX2 Interactome by BioID Reveals EP300 as a Mediator of SOX2-dependent Squamous Differentiation and Lung Squamous Cell Carcinoma Growth

“…Notably, some FDA-approved drugs that contain salicylate moieties inhibit EP300 catalytic activity, including the anti-inflammatory diflunisal, at concentrations that can be achieved in patients (105,133). In addition, natural products including curcumin, anacardic acid, and luteolin, inhibit EP300 catalytic activity (97,98,104), with luteolin also being able to suppress growth of a head and neck SQCC xenograft in mice (104). As suggested by our work, compounds that target EP300 could have therapeutic benefit in lung SQCCs on their own or in conjunction with other treatments.…”

“…EP300 also has a RING finger that autoregulates acetyltransferase activity (96). This architecture allows EP300 to be sensitive to different types of modulatory compounds including distinct research tools, natural products, and FDA-approved drugs (97)(98)(99)(100)(101)(102)(103)(104)(105). Although some previous work has linked EP300 to regulation of SOX2 activity, its inconsistent detection in AP-MS studies and opposing models for regulation of SOX2 did not cause us to consider it prior to our work.…”

Novel extraction techniques and pharmaceutical activities of luteolin and its derivatives

“…In fruits, for example, apple's skin is considered a rich source of luteolin (Mencherini, Picerno, Scesa, & Aquino, 2007). Luteolin abundant plants are widely used in the manufacturing of Chinese traditional medicines for inflammatory, cancer, and hypertension ailments (Selvi et al, 2015). It is mostly found in a bunch of vegetables.…”

Insights into the Roles of Midazolam in Cancer Therapy

“…It plays an essential role in regulating cell growth and division, prompting cells to mature, differentiate, and assume specialized functions, and preventing the growth of cancerous tumors [53]. The p300 protein appears to be critical for normal development before and after birth.…”