Combined AURKA and H3K9 Methyltransferase Targeting Inhibits Cell Growth By Inducing Mitotic Catastrophe

Abstract

The current integrative pathobiological hypothesis states that pancreatic cancer (PDAC) develops and progresses in response to an interaction between known oncogenes and downstream epigenomic regulators. Congruently, this study tests a new combinatorial therapy based on the inhibition of the Aurora kinase A (AURKA) oncogene and one of its targets, the H3K9 methylation-based epigenetic pathway. This therapeutic combination is effective at inhibiting the in vitro growth of PDAC cells both, in monolayer culture systems, and in 3D spheroids and organoids. The combination also reduces the growth of PDAC xenografts in vivo. Mechanistically, it was found that inhibiting methyltransferases of the H3K9 pathway in cells, which are arrested in G2/M after targeting Aurora kinase A, decreases H3K9 methylation at centromeres, induces mitotic aberrations, triggers an aberrant mitotic check point response, and ultimately leads to mitotic catastrophe. Combined, this data describes for the first time a hypothesis-driven design of an efficient combinatorial treatment that targets a dual oncogenic-epigenomic pathway to inhibit PDAC cell growth via a cytotoxic mechanism that involves perturbation of normal mitotic progression to end in mitotic catastrophe. Therefore, this new knowledge has significant mechanistic value as it relates to the development of new therapies, as well as biomedical relevance.

The role of histone methylation in the development of digestive cancers: a potential direction for cancer management

“…Moreover, combination treatment with the pan-H3K9me HMT inhibitor chaetocin and an aurora kinase A (AURKA) inhibitor diminishes H3K9 methylation at centromeres, induces mitotic aberrations, triggers an abnormal mitotic checkpoint response, and ultimately leads to mitotic catastrophe in PC. 222 At the same time, the prospect of arginine methylation as a therapeutic target has been revealed gradually. For example, a recent study found that targeting PRMT5 activity by DW47800 inhibits the malignancy of HCC by downregulating the binding of H4R3me2s to the HNF4α promoter.…”

Combined Targeting of G9a and Checkpoint Kinase 1 Synergistically Inhibits Pancreatic Cancer Cell Growth by Replication Fork Collapse

“…Images were acquired on a Hamamatsu digital camera using AmtV602 image processing software. Immunofluorescence and confocal microscopy were performed as described previously (12). Primary antibodies are indicated in Supplementary Table S1, followed by anti-mouse or anti-rabbit secondary antibody, as appropriate.…”

“…However, most of these agents are being studied within the framework of their gene regulatory activity without taking into consideration their effects during the distinct cell-cycle phases, which we believe to be critical for better understanding cancer. In fact, we have recently shown that arresting cells in G 2 -M with an Aurora kinase A inhibitor while combining them with an inhibitor of the epigenetic H3K9 methylation pathway is an effective approach for altering chromatin structure in a manner that gives rise to an aberrant mitotic checkpoint response leading to rapid death (12). This approach suggested that the capacity of cell-cycle inhibitors could be harnessed to enhance the use of epigenetic inhibitors.…”

Targeting Epigenetic Aberrations in Pancreatic Cancer, a New Path to Improve Patient Outcomes?

“…Similarly, Mathison et al have shown that inhibition of the H3K9 methyltransferase SUV39H1/2, can reduce the growth of PDAC cells in monolayer cells culture, as well as in spheroids, organoids and grafts in vivo. Combined inhibition of AURKA using MLN8237 and H3K9 methyltransferases using a pan-histone methyltransferase inhibitor, chaetocin, induced mitotic catastrophe and proved to be efficacious in preventing progression of the various aforementioned PDAC models [ 61 ]. Gossypol, a chemotherapeutic under investigation, has been used in combination with BRD-4770 to induce autophagy related death [ 50 ].…”