Background: HIF1␣ is a target of anticancer therapy. Results: Lysines within the HIF1␣ N terminus are targets of HDAC4 deacetylation. HDAC4 inhibition causes the increase of HIF1␣ protein acetylation and decrease of protein stability, which lead to the reduction of HIF-1-mediated target gene expressions and activities in cancer cells. Conclusion: HDAC4 provides a novel HIF1␣ regulatory mechanism. Significance: HIF-1 can be targeted by HDAC4 inhibition.
Background: HIF1␣ and p300 are key components of HIF-1 transcription complex. Results: Lysine 709 of HIF1␣ is acetylated by p300, which increases protein stability and HIF-1 activity. Conclusion: p300 has a novel function in stabilizing HIF1␣ by Lys-709 acetylation. Significance: New insights in how HIF1␣ is post-translationally regulated by its cofactor to ensure HIF-1 activity.
Background
Resistance to chemotherapy represents a significant obstacle in prostate cancer therapeutics. Novel mechanistic understandings in cancer cell chemotherapeutic sensitivity and resistance can optimize treatment and improve patient outcome. Molecular alterations in the metabolic pathways are associated with cancer development; however, the role of these alterations in chemotherapy efficacy is largely unknown.
Methods
In a bed-side to bench-side reverse translational approach, we used cDNA microarray and qRT-PCR to identify genes that are associated with biochemical relapse after chemotherapy. Further, we tested the function of these genes in cell proliferation, metabolism, and chemosensitivity in prostate cancer cell lines.
Results
We report that the gene encoding mitochondrial malate dehydrogenase 2 (MDH2) is overexpressed in clinical prostate cancer specimens. Patients with MDH2 overexpression had a significantly shorter period of relapse-free survival (RFS) after undergoing neoadjuvant chemotherapy. To understand the molecular mechanism underlying this clinical observation, we observed that MDH2 expression was elevated in prostate cancer cell lines compared to benign prostate epithelial cells. Stable knockdown of MDH2 via shRNA in prostate cancer cell lines decreased cell proliferation and increased docetaxel sensitivity. Further, MDH2 shRNA enhanced docetaxel-induced activations of JNK signaling and induced metabolic inefficiency.
Conclusion
Taken together, these data suggest a novel function for MDH2 in prostate cancer development and chemotherapy resistance, in which MDH2 regulates chemotherapy-induced signal transduction and oxidative metabolism.
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