Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity, de novo lipogenesis, and prostate cancer growth

ABSTRACT: Prostate cancer (PCa) growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). In this study, we identified lysine methyltransferase (KMT)9 as a novel regulator of PDC activity. KMT9 is localized in mitochondria of PCa cells, but not in mitochondria of other tumor cell types. Mitochondrial KMT9 regulates PDC activity by monomethylation of its subunit dihydrolipoamide transacetylase (DLAT) at lysine 596. Depletion of KMT9 compromises PDC activity, de novo lipogenesis, and PCa cell proliferation, which can be rescued with exogenous KMT9 targeted to mitochondria. Similarly, comparable defects caused by DLAT depletion can be rescued with exogenous DLAT, but not with a methylation-defective DLAT mutant. Concomitant chemical inhibition of de novo lipogenesis and KMT9 depletion more efficiently impair PCa cell proliferation than either treatment alone. Importantly, KMT9 controls PDC activity, de novo lipogenesis, and tumor growth in a PCa mouse model. Finally, in human patients, levels of mitochondrial KMT9 and DLAT K596me1 correlate with Gleason grade. Together, we present a novel mechanism of PDC regulation and the first example of a histone methyltransferase with nuclear and mitochondrial functions. The exceptional dependency on mitochondrial KMT9 allows to develop novel therapeutic strategies to fight PCa.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Prostate Adenocarcinoma

SUBMITTER: Axel Imhof  

LAB HEAD: Axel Imhof

PROVIDER: PXD053942 | Pride | 2024-12-03

REPOSITORIES: Pride