Targeting ACSS2 to Regulate HIF-2α Stability and Suppress ccRCC Growth

Drs. Beckermann, Rathmell, and Bacigalupa discuss their recent research exploring the therapeutic potential of inhibiting ACSS2 to reduce HIF-2α levels, thereby suppressing the growth of ccRCC by disrupting cancer cell metabolism.

They explain why ACSS2 was selected for investigation and its potential as a therapeutic target.

Find their continued discussion here.

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Dr. Beckermann: Thanks, everyone, in the GU Oncology Now community. We’re so happy you’ve joined us. I’m thrilled to be here with two wonderful colleagues and friends of mine, the first and senior authors of an exciting paper recently published in the JCI. This paper provides a better understanding of HIF biology, and there’s a lot of excitement right now about targeting HIF biology with a novel treatment option for patients with kidney cancer. So, I’m excited to welcome Zach, the first author of this paper, and Jeff, the senior author. Zach, could you start off by introducing yourself, and we’ll go from there?

Dr. Bacigalupa: Sure. Thanks, Katy. I’m Zach Bacigalupa. I began in 2018, co-mentored by Kim Rathmell and Jeff. As a postdoc, I have spent the past almost six years working on this project as my primary focus, and we are delighted to share it with everyone now.

Dr. Beckermann: That’s great. And Jeff, I know we’re all part of the same team here, but I would love for you to introduce yourself.

Dr. Rathmell: Sure. I’m Jeff Rathmell, a professor and the director of the Center for Immunobiology. I’ve been working with Zach since he joined our group a few years ago. We have a strong interest in immune function and immune metabolism, which stems from a broader focus on cancer metabolism. Kidney cancer has been a particular area of focus for us, and this paper really launches in that direction.

Dr. Beckermann: Great. Zach, maybe you can start us off by setting the stage. Why did you become interested in investigating ACSS2, and why is it important?

Dr. Bacigalupa: Yeah, it was actually great timing. When I was in graduate school, I studied acetate metabolism and ACSS2 in glioblastoma. As a grad student, I came across some papers from Joseph Garcia’s lab that laid the groundwork, describing fundamental biological systems. These papers highlighted a link between acetate metabolism, ACSS2, and HIF-2, specifically HIF-2, not necessarily HIF-1.

At the time, I hadn’t thought much of it since it didn’t apply to my system in that setting. But when I joined here, I quickly learned that HIF-2 is central to driving clear cell renal cell carcinoma. A lot of light bulbs went off in my head, and I realized I would be studying acetate metabolism again. It seemed like a very clean story, although there ended up being a lot more mechanistic detail that came out of it. It was in line with what I was used to studying, and I had the tools and methods to tackle this project quickly, addressing a crucial need in the kidney cancer community.

Dr. Beckermann: That’s great. And for our audience who may not be familiar with all the details, including some clinicians and medical colleagues, could you share the main findings of your paper?

Dr. Bacigalupa: Well, I think first and foremost, we started off in figure one, where we analyzed some single-cell RNA-seq datasets. The bulk RNA-seq datasets had suggested that ACSS2 had low expression. However, kidney cancer is so heterogeneous, with many different cell types, particularly immune cells, infiltrating the tumors. When we looked at the single-cell dataset, we saw that ACSS2 expression was very low in the immune cells but quite high in the cancer cells. This finding is significant on a broader scale because it highlights the importance of digging deeper into the data. Bulk datasets are useful, but sometimes a more detailed analysis is needed to uncover critical insights related to your research question. I thought that was a crucial takeaway.

Another important element of our findings was that ACSS2 has been described as a promising therapeutic target in breast cancer, brain cancer, and a few others, but it hadn’t been explored in the context of kidney cancer. Given the link to HIF-2 biology that the Garcia lab had previously investigated, but not in kidney cancer, drawing that connection was significant. We found that inhibiting ACSS2, either genetically or pharmacologically, effectively blocked tumor growth. Additionally, we discovered that ACSS2 regulates HIF-2 through two mechanisms. First, at the transcriptional level, likely through epigenetic mechanisms, as ACSS2 acetate metabolism influences histone acetylation, which we confirmed with ATAC sequencing. Second, we observed that ACSS2 also affects HIF-2 protein stability. This dual mechanism of regulating HIF-2 is unique and different from any other approaches currently offered at the clinical level.