David Ann, Ph.D., is interested in the role of post-translational modifications including phosphorylation, acetylation, sumoylation, O-glycosylation and ubiquitination in human cancers, with a particular focus on oncogenesis, metastasis and cancer metabolism. His research team focuses on therapeutic implication of ASS1 (argininosuccinate synthetase 1) in breast cancer biology, and we made several novel discoveries by providing a mechanistic link between ASS1 deficiency, arginine deprivation and lethal chromatin autophagy.
Furthermore, they identify that arginine deprivation as a new potential breast and prostate cancer therapy that targets a subtype of these cancers that has low ASS1 expression. Their results describe how arginine starvation specifically kills tumor cells by a novel mechanism involving mitochondria dysfunction, generation of reactive oxygen species, nuclear DNA leakage and chromatophagy, where leaked DNA is captured and “eaten” by giant autophagosomes. Unlike apoptosis, a cell-death process in which DNA is damaged within the cell nucleus, in chromatin autophagy the nucleus is fragmented and its pieces shuttled off to the lysosome (an organelle within the cell membrane) where the fragments are degraded.
While it has long been recognized that some cancer cells are resistant to apoptosis, they discovered an alternative pathway to induce cell death that overcomes resistance to traditional apoptosis associated with cancer. Their data suggest that arginine depletion results in a decrease of mitochondrial inner membrane and matrix proteins that impairs mitochondrial oxidative phosphorylation (OxPhos) and respiratory function, so-called metabolic stress.
Very recently, they found that metabolic stress by restriction of arginine or glucose or inhibition of fatty acid oxidation leads to KAP1 Ser473 phosphorylation to regulate mitochondrial fusion and fission. Their results define a mechanism of mitochondrial dynamics regulation that operates in cancer cells under metabolic stress to help preserve their survival, with potential therapeutic implications. Their current interest of Dr. Ann’s team is to decipher the signaling transduction pathways and molecular mechanisms underlying adaptive response to metabolic stress.
Specifically, we currently work on (1) mitochondrial dynamics and genome instability, (2) arginine and tumor progression and (3) autophagy and drug resistance.