New finding on proteins helps to find new cancer treatment

Lysine methyltransferases and lysine demethylases are two chromatin-modifying enzymes in the nucleus. In the past, researchers concentrated on the way the enzymes target nuclear proteins. But Rechem et al. assume that there are another important roles the chromatin-modifying enzymes plays outside the nucleus. In order to prove the argument, the team showed that earlier data has implicated chromatin-modifying enzymes as important players in multiple disease states. Thus these enzymes have a possibility of using these enzymes to design drug therapies and are beneficial in disease research.

Rechem et al. investigated chromatin-modifying enzymes in the cytoplasm, and analyzed the lysine demethylase KDM4A, which is a JmjC domain, ontains enzyme and is present both inside and outside of the nucleus. Then they used endogenously immunoprecipitated KDM4A from whole-cell extracts which are derived from cell lines. They adopted a multiplexed quantitative proteomics strategy, using TMT10plex isobaric label reagents and a synchronous precursor selection-based MS3 method on an Orbitrap Fusion Tribrid mass spectrometer equipped with an EASY-nLC 1000 liquid chromatograph and integrated autosampler. They identified interacting proteins from both compartments after matching MS data against a protein sequence database containing all protein sequences in the human UniProt database and that of known contaminants.

Next step they examined proteins interacting with KDM4A using Ingenuity Pathway Analysis (IPA) and got the result that there are proteins related to translation. At the same time, they confirmed the interactions by co-immunoprecipitations with a separate KDM4A antibody. There is also a Western blot that help to confirm that KDM4A can affect translation directly and is present in the initiating fractions of polysome profiles. The team found that reduced KDM4A levels can reduce whole protein synthesis but not change cell proliferation.

The researchers say that KDM4A depletion use chemical inhibition with JIB-04, a JmjC demethylase inhibitor, to prevent translation initiation, reduce overall translation and enhance inhibitor sensitivity. The direct interaction between KDM4A with proteins is involved in translation. It is well-known that mTOR is a first-line defense drug to slow cancer growth by impeding DNA replication, so this finding is considered to be quite earthshaking. KDM inhibition could increase the effectiveness of cancer treatments.

The authors maintain that KDM inhibition could increase the effectiveness of cancer treatments such as mTOR, KDM4A and other JmjC proteins. More research on these protein should be done to develop a more effective cancer therapy.

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