Background

To correct abnormal gene expression in tumor cells, DNA demethylating agents (HMAs) have been introduced into cancer treatment. These drugs inhibit the catalytic activity of DNA methyltransferase 1 (DNMT1), which maintains the methylation pattern of the genome. Notably, HMA administration leads to the unsealing of previously silenced endogenous retroelements (ERVs) within cancer cells. The expressed ERV transcripts form double-stranded RNA in the cell, which the cell recognizes as a viral invasion, thereby inducing a strong immune response. This is referred to as a 'viral mimicry' response and is considered a key to activating anticancer immunity. However, the fact that cancer cells eventually suppress this viral mimicry response and acquire drug resistance has been a major obstacle. It remains unclear how DNMT1 moves on the genome and re-controls abnormal transcription in the drug administration environment. To develop a treatment strategy that maintains efficacy for a longer period, it is necessary to elucidate the molecular switch that causes drug resistance.

Key Findings

The researchers applied Next-Generation Sequencing (NGS) and Chromatin Immunoprecipitation Sequencing (ChIP-seq) to catalytically inhibited cancer cell models. The analysis revealed that, in normal cells, DNMT1 primarily binds to unmethylated CpG island (CGI) regions, which promote gene activation. However, when catalytic activity was forcibly blocked by a demethylating agent, a dramatic redistribution of DNMT1 occurred. As a result of the drug's action, DNMT1, which had lost its activity, moved from its original location in the active CGI region to largely inaccessible, partially methylated regions. This resulted in the massive transcription of unsealed ERVs and mega-intergenic RNAs, leading to a surge in double-stranded RNA in the cell. This induced a viral mimicry response, causing the cell to mistakenly recognize itself as being infected with a virus. The key finding is that cancer cells activate a repair switch to evade this anticancer immune response. The researchers found that some of the DNMT1 that had moved to the inactive region underwent 'SUMOylation,' a process in which it binds to Small Ubiquitin-like Modifier (SUMO). This SUMOylated DNMT1 pool bypassed the drug inhibition and rapidly restored DNA methylation in the inactive region. As methylation was restored, the expression of ERV and mega-intergenic RNA was suppressed, and the viral mimicry response disappeared. This demonstrates that SUMOylation reactivates DNMT1, inducing immune evasion in cancer cells.

Significance and Prospects

This study is of high academic value in that it has identified a new drug target to overcome the limitations of existing DNA demethylating agent therapies. It has provided clues to improve the treatment rate of cancer patients who initially show a good anticancer response but eventually acquire resistance. By inhibiting the SUMOylation pathway simultaneously with HMA administration, the repair mechanism that turns off the viral mimicry response in cancer cells can be completely blocked. This would create an environment in which immune-inducing signals continuously flow from within the tumor, allowing the body's immune system to continuously attack cancer cells. However, additional safety verification is essential before this combination therapy can be applied clinically. This is because SUMOylation is a common metabolic pathway that regulates the physiological function of various proteins in cells. Therefore, a precise drug delivery technology that can block toxicity to normal cells and selectively act on tumors needs to be developed. Securing control technology to safely handle the fine switches of genome regulation is a prerequisite for commercialization.

Why It Matters

This research can be directly applied to a treatment that converts so-called 'cold tumors' with low response rates to immune checkpoint inhibitors in the clinical setting into 'hot tumors.' Representative examples include triple-negative breast cancer and recurrent non-small cell lung cancer that do not respond to chemotherapy or targeted therapies. A treatment plan is designed to administer a combination of existing demethylating agents and new SUMOylation inhibitors to patients. When the drug action unseals the cancer cell genome and ERVs are expressed, the SUMOylation inhibitor completely blocks the activation of the repair switch. As a result, cancer cells that have lost their ability to evade the immune system can only continue to emit viral mimicry signals. These signals stimulate cytotoxic T cells and immune cells, which then migrate to and actively function in the tumor tissue. As a result, the tumor microenvironment is converted into an immune-friendly environment, significantly enhancing the therapeutic efficacy of existing immune checkpoint inhibitors. In the bio-pharmaceutical industry, this is expected to be a good opportunity to expand the therapeutic area of SUMOylation inhibitors, which are currently in the clinical stage.