A few years delayed, but the issue remained: how do enzymes that modify histones contribute to cancer, and can we apply that knowledge to better understand mechanisms of tumorigenesis or to develop therapies?

Gathered in a remote part of Tennessee, at a lovely secluded historic mill and resort, complete with a hike to a massive waterfall, we wrestled with topics that discretely play out in our cells every minute. We opted to have an entirely in-person meeting, thinking that the in-person engagement would be the most effective. With a few last-minute cancelations due to COVID travel issues, we were able to add several early career faculty guests whose work was complementary; their presence in fact made the program truly outstanding. The success of a Forbeck Forum comes down to three things: 1) An engaged set of participants who are engrossed in the topic during the sessions and in between—at meals, while hiking, in the evening when socializing, 2) A topic that has a lot of facets that are relevant to human physiology and cancer, and a group willing to approach with openness—an open mind to consider outside the box concepts, and openness to share opinions, ideas, and expertise, and 3) A cohort of early career researchers who are energized, excited for the future, and enthusiastic about the careers they are launching into—and the community of investigators that they are joining.

The meeting was launched by co-chair Brian Strahl, PhD, an original discoverer of the histone code, showcasing a new function for histone methyltransferase, SETD2, as a structural element interacting with nuclear features independent of its well-known catalytic function “writing” trimethylation on histone H3, lysine 36 (H3K36). SETD2 was a popular enzyme in this forum, and its varied activities emerged as a theme of the meeting, as well as its potential for therapeutic targeting vs acting as a major guardian of the cell. Histone marks such as the one laid down by SETD2, are interpreted by a variety of “reader” molecules, and Mark Bedford, PhD, revealed potential for many new readers that may interpret histone methylation by H3K36 enzymes. These epigenetic marks maintain the genome, until portions of the genome are aberrantly activated, a process important in overlapping functions between viral response and cancer, as detailed by scholar Charles Isak, PhD. We learned intricate details of the interactions between marks shared and exclusive to histones and nucleosome by Nick Young, PhD. Matthew Lorincz, PhD, shared critical information on the delicate orchestration of these marks in determining cell identities and fates. Scholar Michael Meers, PhD, introduced the concept that transcription factors might take advantage of epigenetic changes, functionally “highjacking” the genome. Our first day was concluded with a return to SETD2, and Jerry Workman, PhD, sharing insights into the domain specificity of this multifunctional protein. On day two, we learned from Frank Mason, PhD, that when SETD2 is deleted, as occurs in a variety of cancers, that its loss leads to the loss of genomic integrity. Additional insight by co-chair Kimryn Rathmell, MD, PhD showed that SETD2 functions in the non-genic space and its loss further contributes to the phenotype of cancer cells.

Noncanonical targets in the cell, namely the cytoskeleton, were discussed by Cheryl Walker, PhD, as a further source of genomic instability. Factors regulating SETD2 itself were discussed by Ruhee Dere, PhD. Two talks on strategies to pharmacologically take advantage of vulnerabilities placed by SETD2 loss were presented by scholars Aguirre de Cubas, PhD, and Josh Jang, PhD. Or Gozani, MD, PhD, shared mechanisms that cancer cells use to amplify enzymes in this pathway, and Tatiana Kutateladze, PhD, took us on a tour of the detailed structural domains of proteins regulating and reading histone methylation. Finally, Peter Lewis, PhD, used mutations found in cancers that alter the histones themselves to teach us more about the interactions and regional specificity of these histone marks that brought us full circle. There are opportunities to use the histone code to understand the cellular protections that prevent cancer, and key vulnerabilities that we explored as future therapeutics when those protection are disrupted. There are functions that are contentious, and more remaining to be discovered, as we seek to understand this process as it relates to human cancer.

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