The Role of Epigenetic Therapy for Non-Small-Cell Lung Cancer

Epigenetic alterations (global DNA hypomethylation, regional DNA hypermethylation and aberrant histone modification) can influence the expression of oncogenes and lead to development and progression of tumors. Recent progresses in the treatment of advanced non-small-cell lung cancer (NSCLC) have focused on the discovery that selective inhibition of driver mutations, in genes to tumor growth and proliferation, may lead to dramatic clinical responses.

For example, the epigenetic therapy has led to the approval of agents targeting two of these molecular aberrations, mutations occurring in the epidermal growth factor receptor (EGFR) gene or translocations affecting the anaplastic lymphoma kinase (ALK) gene. Among strategies for the treatment of NSCLC, epigenetic therapy is of particular interest as it may have efficacy for tumors that are not used to traditionally pathways or mutations. This study pays attention on potential epigenetic targets in NSCLC and discusses results from early phase clinical trials.

For the reason of limited activity of single agent epigenetic therapy and the complications associated with DNMT inhibitors at cytotoxic doses, including extended reduction in the number of blood cells and consequent loss of dose intensity, the potential for combination low dose epigenetic therapy has been explored.

Patterns of histone posttranslational modifications (PTMs) must be reconstructed after passage of the replication fork to restore the correct epigenetic status to each region of the genome, Histone variants have been proposed to act as determinants for PTMs with general regulatory functions. Here, ATXR5 is identified as a histone-modifying enzyme, which can selectively methylate the replication-dependent histone H3 variant H3.1.

The histone H3 Lys27(H3K27) methyltransases ATXR5 and ATXR6 thought to maintain the heterochromatic markK27me1 during DNA replication. In plants atxr5 atxr6 double mutants, H3K27me1 levels reduced and heterochromatin is decondensed. Using the histone lysine methyltransferase (HKM)Assays, it is found that ATXR5/6 have much higher activity on nucleosomes containing H3.1 than H3.3. The crystal structure suggests that both SET and selleckchem nSET of RcATXR5 are involved in selectiveH3.1 binding.

This study suggests a model for the mitotic inheritance of the heterochromatic mark H3K27me1 and the protection ofH3.3-enriched genes against heterochromatization during DNA replication. To summary, this work demonstrates that histone variants can determine epigenetic states through direct modulation of chromatin-modifying enzyme activity. And more, the ability of ALK inhibitor ATXR5/6 to distinguish between the variants H3.3 and H3.1 offer a mechanism for the mitotic inheritance and genome-wide distribution of H3K27me1 in plants.