A pre-clinical study led by researchers at The University of Kansas Medical Center demonstrated in recent publication in Gastroenterology that histone lysine demethylase 3A (KDM3A) is upregulated in pancreatic tumors, and hypoxia-inducible factor 1[alpha] (HIF1[alpha]) played a significant role for increased expression of KDM3A in pancreatic ductal adenocarcinoma (PDAC) (2019;157(6):1646-1659.e11). The KDM3A demethylates histone marks H3K9me1 and H3K9Me2 to increase gene transcription in pancreatic tumors and showed its regulation of gene encoding double calmodulin-like kinase 1 (DCLK1), a well-known marker of pancreatic cancer stem cells (CSC). It has been demonstrated that knockdown of KDM3A in pancreatic cancer cells significantly reduced malignant properties and slowed growth of orthotopic tumors in mice. Overexpression of KDM3A induced transformation in non-cancerous pancreatic ductal cells, including significant growth in orthotopic tumors in mice.
The binding sites of KDM3A have been identified in DCLK1 promoter that transcriptionally regulates expression of DCLK1, whereas the DCLK1 levels were reduced due to the knockdown of KDM3A. KDM3A demethylates mainly repressive marks of H3K9me1 in PDAC, which is presumably the mechanism regulating malignant properties. This study describes a new role for KDM3A in the regulation of DCLK1, as well as stemness and progression in PDAC. This newly described molecular mechanism appears especially relevant to the hypoxic environment of PDAC (Figure). Given the aggressiveness of PDAC, understanding the roles of epigenetic marks in PDAC malignancy could have important implications for the regulation of pathways promoting PDAC progression.
"Pancreatic ductal adenocarcinoma is a lethal malignancy and is the fourth leading cause of cancer-related mortality in the U.S., due to its susceptibility to metastasis," noted Animesh Dhar, PhD, principle investigator of this work, and Associate Professor of Cancer Biology at the University of Kansas Cancer Center. "Nothing is available right now."
This research revealed the understanding of a new role for histone demethylase KDM3A as a specific target in regulation of DCLK1, as well as PDAC stemness and progression. This newly described molecular mechanism appears especially relevant to the hypoxic environment of PDAC because hypoxia (HIF1[alpha]) binding to hypoxia-responsive element (HRE) in KDM3A induces oncogenic potential in pancreatic ducal cells (Figure). In this work, it has also been reported in spontoons pancreatic cancer mice model that KDM3A and DCLK1 showed a positive correlation between KDM3A with DCLK1 expression in pancreatic intraepithelial neoplasia (PanIN), premalignant lesion, and tumor tissue derived from Kras mutation (KPC) mice.
The work is important and timely due to the work of Sir Peter Ratcliffe, MD, a 2019 Nobel Laureate of Physiology and Medicine, on HIF1[alpha] regulating oxygen sensing machinery for cellular proliferation. The study published in Gastroenterology demonstrated that cooperation between HIF1[alpha] and KDM3A to control hypoxia-induced stemness via upregulation of DCLK1 and the inhibitory effect of KDM3A in PDAC will be an effective strategy. By targeting specifically, the KDM3A that regulated by hypoxia for development of pancreatic cancer could be a novel approach.
Hence, the development of inhibitors to this regulatory pathway may provide new opportunities for therapeutic targeting of PDAC via KDM3A. Dhar also mentioned that the group has been developed PNSA, novel specific analogue of N-oxalyl glycine (NOG), a putative non-specific inhibitor of histone lysine demethylases derived from spinach, and PNSA can directly bind specifically to KDM3A and showed significant reduction of KDM3A regulating PDAC stemness as described in this work in Gastroenterology (Figure). PNSA treatment also reduced DCLK1 and KDM3A protein expression not only in human pancreatic cells, but also significant pancreatic tumor reduction in mice. This inhibitory effect of PNSA, novel NOG analogue, will have profound therapeutic implication in the future.
Given the aggressiveness of PDAC, understanding the roles of epigenetic marks, particularly KDM3A in PDAC malignancy, could have important therapeutic implications for the regulation of pathways through hypoxia promoting PDAC progression. Cancer researchers can build on these findings to continue uncovering ways to treat PDAC by targeting KDM3A using NOG analogue PNSA, that could have been implicated with high specificity as therapeutic agents for phase I clinical trial in near future.
Meet the Winner of the Nobel Prize
"Sir Peter J. Ratcliffe, MD, Nobel Laureate" has an impressive ring to it. But the fact that this British knight is one of three joint recipients of the 2019 Nobel Prize in Physiology or Medicine does little to sway his course. A member of the Oxford Branch of the Ludwig Institute for Cancer Research in England, Sir Peter shows up daily with one thing on his mind-scientific discovery. Read more about Ratcliffe's accomplishments here: https://bit.ly/2tm1NI8