Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes

Area of Science:

• Oncology
• Epigenetics
• Immunology

Background:

• Epigenetic therapy can derepress transposable elements (TE), activating anti-cancer immune responses.
• The precise mechanisms of TE regulation by chromatin modifier enzymes (CME), particularly concerning p53 status, remain unclear.

Purpose of the Study:

• To investigate the molecular mechanisms of TE regulation by distinct CMEs in various cancer types with different p53 statuses.
• To evaluate the efficacy of FDA-approved epigenetic drugs in modulating TE expression and subsequent immune activation.

Main Methods:

• Systematic inhibition of distinct CMEs using FDA-approved epigenetic drugs in p53 wild-type and mutant colorectal, esophageal, and prostate cancer cell lines.
• Analysis of TE subfamily derepression patterns in response to CME inhibition.
• Assessment of the impact of p53 status on TE activation and immune response.

Main Results:

• Distinct TE subfamilies were derepressed in a cell type-specific manner upon inhibition of different CMEs.
• Co-inhibition of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) (DNMTi-HDACi) demonstrated the most consistent TE derepression across cancer types.
• Loss of p53 led to enhanced TE activation and chimeric transcript expression, primarily via non-genomic p53 actions.
• DNMTi-HDACi induced a robust immune response, linked to increased inverted repeat Alu expression and decreased ADAR1-mediated Alu RNA editing.

Conclusions:

• Epigenetic drug combinations, particularly DNMTi-HDACi, can effectively derepress specific TEs and elicit immune responses in cancer cells.
• p53 status significantly influences TE activation, with loss of p53 potentiating this effect.
• These findings offer insights for the rational application of epigenetic therapies tailored to distinct cancer types and p53 mutational profiles.