Succinylation and redox status in cancer cells

Abstract

Succinylation is a post-translational modification (PTM) event that associates metabolic reprogramming with various pathological disorders including cancers via transferring a succinyl group to a residue of the target protein in an enzymic or non-enzymic manner. With our incremental knowledge on the roles of PTM played in tumor initiation and progression, relatively little has been focused on succinylation and its clinical implications. By delineating the associations of succinylation with cancer hallmarks, we identify the, in general, promotive roles of succinylation in manifesting cancer hallmarks, and conceptualize two working modes of succinylation in driving oncogenic signaling, i.e., via altering the structure and charge of target proteins towards enhanced stability and activity. We also characterize succinylation as a reflection of cellular redox homeostatic status and metabolic state, and bring forth the possible use of hyper-succinylated genome for early cancer diagnosis or disease progression indication. In addition, we propose redox modulation tools such as cold atmospheric plasma as a promising intervention approach against tumor cells and cancer stemness via targeting the redox homeostatic environment cells established under a pathological condition such as hypoxia. Taken together, we emphasize the central role of succinylation in bridging the gap between cellular metabolism and redox status, and its clinical relevance as a mark for cancer diagnosis as well as a target in onco-therapeutics.

WITHDRAWN: AMPK α Succinylation modification of protein K266 enhances lipid metabolism and promotes growth of non-small cell lung cancer cells

“…Our experiments con rmed that the AMPKα1 protein interacts with HAT1 and SIRT5, further revealing the molecular mechanism regulating AMPKα1 succinylation. HAT1 is a histone succinyltransferase that regulates the succinylation of various proteins, and its high expression promotes the occurrence of multiple types of cancer [19]. However, the mechanism mediated by HAT1-induced succinylation during tumour development remains unknown.…”

Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways

“…Succinylation correlates with increased PD-L1 expression in prostate cancer, suggesting its significant role in regulating PD-L1 levels [ 118 – 121 ]. Additionally, lactic acid, a precursor of histone lysine modifications, is linked to glycolytic gene activation by STAT5 in AML, leading to increased PD-L1 transcription via enhanced histone lactylation and nuclear translocation of E3BP [ 122 , 123 ].…”

SIRT5 promote malignant advancement of chordoma by regulating the desuccinylation of c-myc

“…Nowadays, succinylation is considered as a PTM widely present in prokaryotes and eukaryotes, and plays vital roles in regulating various physiological or pathological functions including signaling pathways, mitochondrial metabolism, and energy metabolism [ 11 ]. Succinylation works by regulating the structure of the protein by transferring the succinyl group (-CO-CH 2 -CH 2 -CO 2 H) to the residue of the target protein [ 12 ]. Interestingly, the effects of succinylation on the structure and function of target proteins may be greater than that of other PTMs [ 12 ].…”

“…Succinylation works by regulating the structure of the protein by transferring the succinyl group (-CO-CH 2 -CH 2 -CO 2 H) to the residue of the target protein [ 12 ]. Interestingly, the effects of succinylation on the structure and function of target proteins may be greater than that of other PTMs [ 12 ]. Previous studies have demonstrated the role of succinylation in various diseases, including cancers [ 13 – 15 ].…”