Expression ofMTAPInhibits Tumor-Related Phenotypes in HT1080 Cells via a Mechanism Unrelated to Its Enzymatic Function

Abstract

Methylthioadenosine Phosphorylase (MTAP) is a tumor suppressor gene that is frequently deleted in human cancers and encodes an enzyme responsible for the catabolism of the polyamine byproduct 5′deoxy-5′-methylthioadenosine (MTA). To elucidate the mechanism by which MTAP inhibits tumor formation, we have reintroduced MTAP into MTAP-deleted HT1080 fibrosarcoma cells. Expression of MTAP resulted in a variety of phenotypes, including decreased colony formation in soft-agar, decreased migration, decreased in vitro invasion, increased matrix metalloproteinase production, and reduced ability to form tumors in severe combined immunodeficiency mice. Microarray analysis showed that MTAP affected the expression of genes involved in a variety of processes, including cell adhesion, extracellular matrix interaction, and cell signaling. Treatment of MTAP-expressing cells with a potent inhibitor of MTAP’s enzymatic activity (MT-DADMe-ImmA) did not result in a MTAP− phenotype. This finding suggests that MTAP’s tumor suppressor function is not the same as its known enzymatic function. To confirm this, we introduced a catalytically inactive version of MTAP, D220A, into HT1080 cells and found that this mutant was fully capable of reversing the soft agar colony formation, migration, and matrix metalloproteinase phenotypes. Our results show that MTAP affects cellular phenotypes in HT1080 cells in a manner that is independent of its known enzymatic activity.

Characterization of MTAP Gene Expression in Breast Cancer Patients and Cell Lines

“…However, Dou et al [ 23 ] observed an inverse correlation between cellular differentiation and MTAP relative expression in colorectal cancer, mainly due to promoter demethylation in more malignant tumors. Tang et al [ 24 ] demonstrated that the tumor suppressor function of MTAP in HT1080 fibrosarcoma cells is not the same as its known enzymatic function.…”

Independent Loss of Methylthioadenosine Phosphorylase (MTAP) in Primary Cutaneous T-Cell Lymphoma

“…However, the apparent selection pressure for subclones with loss of MTAP in skin and retention of MTAP in the peripheral blood of patients with SS is intriguing and remains to be explained but could reflect a role for the skin microenvironment that is not present in the peripheral blood. Interestingly, a recent study suggested that MTAP may act as a tumor suppressor independently of its enzymatic function (Tang et al, 2014); however, the precise mechanism remains unclear. Analysis using additional Q-PCR probes demonstrated 75% and 58.3% concordance for MTAP and CDKN2A, respectively, between probe sets 1 and 2.…”

Loss of 5′-Methylthioadenosine Phosphorylase (MTAP) is Frequent in High-Grade Gliomas; Nevertheless, it is Not Associated with Higher Tumor Aggressiveness

“…This protein is expressed virtually in all tissues throughout the body, and its homozygous deletion is frequently associated with solid and hematologic tumors such as mesothelioma, lung carcinoma, hepatocellular carcinoma, gastrointestinal stromal tumors, metastatic melanoma, leukemias, and lymphoma [18,[21][22][23][24][25]. Therefore, MTAP has been reported as a tumor suppressor gene [24,[26][27][28][29][30]; however, many studies have demonstrated the contradictory function of MTAP. For instance, the loss of MTAP expression has been associated with inhibition of growth and progression of head and neck carcinoma and lung cancer by MTA accumulation [31,32].…”