Andrea Miyahira: Hi, everyone. I'm Andrea Miyahira at the Prostate Cancer Foundation. Today, I'm joined by Dr. Housheng He and Dr. Xin Xu of Princess Margaret Cancer Centre in Canada. They will discuss their new paper, "The Landscape of m6A in Localized Primary Prostate Cancer," published in Nature Genetics. Dr. He and Doctor Xu, thank you for joining.

Housheng Hansen He: Thank you.

Xin Xu: Thank you. Hi. I'm Xin Xu, from Hansen He Lab at Princess Margaret Cancer Centre. I'm going to briefly highlight our recent Nature Genetics study, which maps the m6A epitranscriptome in localized prostate cancer, and uncovers how it connects germline risk to tumor evolution and therapeutic vulnerabilities. m6A is the most abundant internal modification on mRNA. It can be dynamically regulated by three groups of proteins, writers, erasers, and readers.

It plays critical regulatory roles in almost every step during an RNA life cycle, from transcription to degradation.

In cancer, m6A regulators are often dysregulated. Some act as oncogenes, others act as tumor suppressors. This highlights the potential importance of m6A modifications in cancer development and progression.

In prostate cancer, we already have extensive knowledge of the genome, epigenome, transcriptome, and proteome, but the epitranscriptome remains largely unknown.

To fill this gap, we profiled 162 tumor samples with matched DNA, RNA, and protein using the refined meRIP‑seq method that was developed by our lab. Our analysis revealed five molecular subtypes defined by global m6A patterns. These subtypes not only differ in terms of aggressiveness and genomic instability, but also show significant differences in clinical outcomes.

For instance, hypoxic tumors characterized by low‑oxygen stress display a distinct m6A signature, suggesting that m6A helps tumors adapt to their microenvironment.

Most importantly, these m6A‑based subtypes are closely associated with prognostic indicators, showing promise for m6A as a predictive biomarker for clinical outcomes in prostate cancer patients.

We also discovered m6A‑QTLs, which are germline variants that influence m6A abundance. In total, 97 such variants were associated with RNA abundance, 9 with protein levels, and 4 with both.

In addition, several key m6A regulators are also frequently dysregulated. These insights point to m6A regulation as a novel and actionable vulnerability in prostate cancer.

Finally, we identified VCAN as a key m6A‑regulated oncogene in prostate cancer. m6A modifications on this mRNA were strongly linked to poor prognosis. It predicts recurrence better than its mRNA or protein abundance. We then tested VCAN's function both in vitro and in vivo.

When we used a targeted RNA‑editing tool to install m6A at this site, we saw VCAN mRNA and protein levels increase, and the cancer cells became more invasive.

Then we identified that this m6A site is recognized by the IGF2BP3 protein, which helps stabilize the transcript and boost translation.

Together, these results show how a single m6A site can directly drive tumor growth, making VCAN a promising therapeutic target. To summarize, we generated the first m6A landscape of localized prostate cancer, adding a new layer to how we understand prostate tumor heterogeneity and progression.

Second, m6A patterns outperform some traditional biomarkers and may aid in clinical decision‑making.

And third, therapeutically targeting m6A, either through editing or modulating its enzymes, could open new precision strategies.

I'd like to thank our co‑first authors Helen Zhu, Rupert Hugh‑White, and Julie Livingstone, and all our collaborators for their invaluable contributions.

And we're also grateful to the Prostate Cancer Foundation for their generous support, and to UroToday for the opportunity to share our work. Thank you, and I look forward to the discussion.

Andrea Miyahira: Thank you so much, Dr. Xu, for sharing that. So molecular tumor subtyping has been largely based on genomics, such as certain driver gene alterations. How does this data change our approach to molecular tumor subtyping? For instance, can tumors be better grouped based on clinical outcomes or treatment responses with the inclusion of epitranscriptomic data?

Xin Xu: Yeah. That's a great question. Our study adds an epigenetic layer to prostate cancer subtyping by profiling m6A in these tumors. We identified five distinct subtypes linked to recurrence risk, genomic instability, and hypoxia. These subtypes offer prognostic value beyond genomics and reflect tumor behavior not captured by DNA alone. So yes, integrating m6A helps better group tumors based on clinical outcomes.

Andrea Miyahira: That's really awesome. So are m6A regulatory enzymes altered in prostate cancer? And if so, by mutation or how, and how frequent are they?

Xin Xu: Yes. m6A regulatory enzymes, including writers, erasers, and readers, are frequently altered in prostate cancer, with the alteration rate ranging from about 10% to 30%. This alteration suggests that m6A dysregulation is a frequent and important feature of prostate cancer biology.

Andrea Miyahira: Thank you. So would targeting m6A dysregulation have any therapeutic value? And does your work suggest any new therapeutic targets or opportunities?

Housheng Hansen He: Yes. So our work does suggest that targeting m6A modification itself or the regulators—the writer, reader, and eraser enzymes—could be promising therapeutic approaches. In particular, we found that the readers and the writers are frequently mutated in prostate cancer patients; in particular, the readers are amplified in about 30% of prostate tumors, so that does provide a potential for targeting those readers.

Andrea Miyahira: OK, thanks. And what are your next steps?

Housheng Hansen He: So the next steps are a few aspects. First, we're extending the m6A profiling into metastatic patient tumors to identify modifications that are associated with drug resistance and metastasis. And then second, Xin developed a base‑editing‑based screening approach so we can systematically analyze the importance of each individual m6A modification that we identified.

And third, we're developing therapeutic approaches to target either the modification or the enzyme, as I mentioned, in particular for the readers. So our collaborators have developed small‑molecule inhibitors targeting the reader YTHDF1, and we're testing their efficacy in prostate cancer.

Andrea Miyahira: OK. Well, thank you so much, Dr. He and Dr. Xu, for sharing all of this with us today. And I hope our listeners will also tune in to the accompanying interview with Dr. He and Dr. Teng.

Housheng Hansen He: OK, thank you.

Xin Xu: Thank you.