Influence of sulforaphane, an inhibitor of histone deacetylases on the genomic instability and epigenetic mechanisms in human cell lines

Author(s)

Patrick Wellington da Silva dos Santos

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
• Defense date: 2019-03-22

Examining board members

Lusania Maria Greggi Antunes; Andre Luiz Pedrosa; Denise Crispim Tavares

• Advisor: Lusania Maria Greggi Antunes; Alexandre Ferro Aissa

Abstract

Sulforaphane is an isothiocyanate found in cruciferous vegetables and is a potent inhibitor of carcinogenesis. However, the molecular mechanisms by which sulforaphane affects cancer cells are still not fully understood. Thus, a comprehensive cellular and molecular investigation were conducted in this study to evaluate the effects of sulforaphane on hepatocarcinoma cells, HepG2 and human primary gastric cells, GAS. The results demonstrated the antioxidant potential of sulforaphane at low concentrations and cytotoxic effects, reducing cell viability in both cell lines at higher concentrations. The RNA-Seq analysis allowed to identify the influence of sulforaphane in several signaling pathways. Cell cycle arrest in G2/M and increased expression of cyclin-dependent cyclins and kinases (CDK) suggest that sulforaphane induces mitotic block in HepG2. Sulforaphane induced DNA damage in HepG2, and this genotoxic effect may be related to inhibition of histone deacetylases (HDAC) since these chromatin profile controlling enzymes were found downregulated. The DNA damage caused by sulforaphane may have induced cell cycle arrest and cell death by apoptosis. Sulforaphane induced apoptosis and triggered pro-apoptotic signals in both cell lines. The downregulation of MAPK / ERK / JUN and PIK3 / AKT signaling pathways may be related to reduced cell proliferation observed in HepG2 by the clonogenic assay. Finally, sulforaphane altered the methylation pattern in both strains, which may be related to the silencing of motifs of transcription factors related to proliferation and tumor growth. The data presented include an overview of the influence of sulforaphane on several anticancer mechanisms and may serve as a resource for future studies (AU)

• FAPESP's process: 16/14703-1 - Influence of sulforaphane, an inhibitor of histone deacetylases on the genomic instability and epigenetic mechanisms in human cell lines
• Grantee: Patrick Wellington da Silva dos Santos
• Support Opportunities: Scholarships in Brazil - Master