The deacetylation-phosphorylation regulation of SIRT2-SMC1A axis as a mechanism of antimitotic catastrophe in early tumorigenesis

Abstract

Improper distribution of chromosomes during mitosis can contribute to malignant transformation. Higher eukaryotes have evolved a mitotic catastrophe mechanism for eliminating mitosis-incompetent cells; however, the signaling cascade and its epigenetic regulation are poorly understood. Our analyses of human cancerous tissue revealed that the NAD-dependent deacetylase SIRT2 is up-regulated in early-stage carcinomas of various organs. Mass spectrometry analysis revealed that SIRT2 interacts with and deacetylates the structural maintenance of chromosomes protein 1 (SMC1A), which then promotes SMC1A phosphorylation to properly drive mitosis. We have further demonstrated that inhibition of SIRT2 activity or continuously increasing SMC1A-K579 acetylation causes abnormal chromosome segregation, which, in turn, induces mitotic catastrophe in cancer cells and enhances their vulnerability to chemotherapeutic agents. These findings suggest that regulation of the SIRT2-SMC1A axis through deacetylation-phosphorylation permits escape from mitotic catastrophe, thus allowing early precursor lesions to overcome oncogenic stress.

New Activities of the Nuclear Pore Complexes

“…Our laboratory also explored additional functions of NPCs beyond nuclear transport [14,15] and found that nucleoporins Rae1 [16,17], Tpr [18][19][20], Nup358/RanBP2 [21], Nup62 [22], Nup58 [23], and Nup88 [24] play critical roles in maintaining spindle bipolarity, centrosome and mid-body homeostasis during cell division [25,26]. For instance, we provided several lines of evidence that the phosphorylation of the cohesin subunit, SMC1, stimulates binding to mitotic Rae1 [27,28], a phenomenon recently confirmed by others to form part of a mechanism of antimitotic catastrophe in early tumorigenesis [29]. Indeed, Rae1 is highly overexpressed in colon cancer [30].…”

Inhibition of SIRT2 promotes APP acetylation and ameliorates cognitive impairment in APP/PS1 transgenic mice

“…Western blotting was performed as previously described (Yi et al, 2021). Cells or tissues were lysed with modified lysis buffer (150 mM NaCl, 1 mM NaF, 50 mM Tris-HCl (pH 7.6), 1 mM EDTA, 1 mM Na 3 VO 4 , 1% NP-40, 1 mM MgCl 2 , 1 mM DTT, 1 mM NaF, 0.25% sodium deoxycholate) containing protease inhibitor cocktail (Sigma) and 1 mM phenylmethylsulfonyl fluoride (PMSF) on ice and then subjected to a BCA assay (Pierce).…”

Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics

“…As a member of class III histone deacetylates, SIRT2 catalyzes the nicotinamide adenine dinucleotide (NAD + )-dependent removal of acyl groups from lysine residues of substrates. − SIRT2 is one of the key regulators of post-translational modifications of many proteins. ,− Aberrant activity of SIRT2 has been related to neurodegenerative diseases, cancer, and metabolic syndrome. , A growing body of evidence suggests that pharmacological modulation with SIRT2 inhibitors holds promise for cancer chemotherapy and chemoprevention. − Triple-negative breast cancers (TNBCs), a subgroup of breast malignancies defined as cancers lacking the expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2, represent highly invasive carcinomas with high metastatic potential, proneness to relapse, and poor prognosis . TNBCs have been frequently linked to SIRT2 overexpression .…”