HDAC7-driven metabolic remodeling in renal tumor progression

Renal cell carcinoma (RCC) is among the 10 most common malignancies in both men and women. It is also a malignancy that is prevalent in the Veteran population. An analysis of VA Central Cancer Registry (VACCR) data demonstrates that cancer of the kidney is among the most common cancers in the veteran population. The most common histology is clear cell RCC (ccRCC), the focus of this proposal. One-third of patients will develop metastasis. Unfortunately, most patients who develop metastasis will die from their disease. These realities have created two fundamental gaps: 1) what are the mechanisms that mediate aggressive behavior in RCC? and 2) can we target these mechanisms? The goals of this proposal will be to address these major gaps in the field to improve outcome for Veterans, as well as the greater population afflicted with RCC. The kidney is among the most metabolically active organs in the human body. Notably, RCC harbors dramatic alterations in metabolic gene expression programs. The most well-studied metabolic pathway in RCC is glycolysis as the expression of enzymes that mediate this pathway are upregulated due increased expression of hypoxia inducible factor (HIF). However, an equally compelling phenotype is our data demonstrating dramatically reduced expression of enzymes that mediate the catabolism (i.e., breakdown) of branched chain amino acids (BCAAs). BCAAs are essential amino acids, and therefore must be obtained from the diet. BCAA catabolism occurs in the mitochondria and consists of a complex series of reactions that mediate the breakdown of valine, leucine, and isoleucine. Amongst all tumor types, loss of the BCAA catabolism program is most strongly associated with death for patients with kidney cancer. Despite this compelling link, the mechanisms that drive this remodeling and its impact on tumor biology are poorly understood. The objective of this proposal is to identify the key drivers of metabolic remodeling and the molecular underpinnings by which this remodeling propels tumor progression. Elucidating this molecular connection will yield novel strategies to counter tumor progression which would improve patient outcomes. Our preliminary data uncover a novel role for the epigenetic factor histone deacetylase 7 (HDAC7) in suppressing the BCAA catabolic gene expression program in RCC. Our data indicate this reroutes BCAAs toward protumorigenic pathways based on our findings demonstrating that HDAC7 inhibition restores expression of BCAA catabolism enzymes and suppresses tumor growth in vivo. In turn, our data uncover a novel role for BCAAs in the activation of signaling nodes that promote aggressive behaviors in cancer cells. These data have led us to propose the novel hypothesis that HDAC7 reprogramming of BCAA metabolism drives RCC progression This central hypothesis, based on strong preliminary data, will be tested through pursuit of the following specific aims: 1) determine the epigenetic basis by which BCAA catabolism is suppressed in kidney cancer, 2) determine the role of suppressed BCAA catabolism in renal carcinogenesis, and 3) determine novel signaling roles for BCAAs that promote aggressive tumor behavior. We will delineate how diet, the epigenome, and metabolism interact to activate downstream signaling events critical to renal tumor growth and progression. By dissecting these molecular mechanisms and demonstrating their significance, we expect to identify novel opportunities for intervention to improve outcomes for veterans impacted by kidney cancer.