KMT9 Is an Epigenetic Writer That Controls Prostate Cancer Cell Growth

Methylation of lysine residues in histone tails modulates a variety of physiologic processes, including transcriptional regulation, and has been shown to be mediated by the SET domain family of methyltransferases or by DOT1L, a member of the seven-β-strand family. Metzger, Wang, and colleagues sought to determine whether other members of the seven β-strand family also function as histone lysine methyltransferases. Among those family members with amino acid sequence similarity to DOT1L, N-6 adenine-specific DNA methyltransferase 1 (N6AMT1, also known as C21orf127) heterodimerized with tRNA methyltransferase subunit 11-2 (TRMT112), and this complex, termed lysine methyltransferase 9 (KMT9), possessed histone methyltransferase activity. Mapping studies revealed that C21orf127–TRMT112 exclusively monomethylates histone H4 at Lys12 (H4K12me1). A crystal structure of cofactor- and substrate-bound C21orf127–TRMT112 uncovered that heterodimerization was necessary for S-adenosyl-methionine binding and histone methyltransferase activity. Both KMT9 and H4K12me1 were detected in normal human prostate and prostate tumors, and KMT9 expression levels were increased in advanced tumors and metastatic lesions. Analysis of KMT9 chromatin occupancy revealed that KMT9 localization was enriched at the promoters of genes encoding cell-cycle regulators and correlated with H4K12me1 levels. KMT9 knockdown reduced the expression of these genes, and this decrease was associated with diminished H4K12me1 and RNA Pol II levels at the promoters of these genes, implicating KMT9 in regulating transcription initiation. Furthermore, KMT9 depletion impaired the proliferation of both androgen-dependent and androgen-independent castration-resistant prostate cancer cells and strongly reduced the growth of prostate tumor xenografts, including enzalutamide-resistant tumors. Of note, KMT9 depletion did not affect the proliferation of non–prostate cancer cell lines, suggesting that the role of KMT9 may be cell type–dependent. Collectively, these data identify KMT9 as a writer of the H4K12me1 histone mark and suggest a potential androgen receptor–independent avenue for therapeutic intervention in castration-resistant prostate cancer.

Metzger E, Wang S, Urban S, Willmann D, Schmidt A, Offermann A, et al. KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells. Nat Struct Mol Biol 2019;26:361–71.

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