SIRT2 mediated downregulation of FOXM1 in response to TGFβ through the RAF-MEK-ERK signaling pathway in colon cancer

Ozkan Ozden,Seong-Hoon Park

doi:10.2298/abs210227020o

Ozkan Ozden, Seong-Hoon Park

Open Access

https://doi.org/10.2298/abs210227020o

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Abstract

The transcription factor forkhead box M1 (FOXM1) is frequently upregulated in many solid tumors, including those in the colon. As a master regulator, the sirtuin (SIRT) protein family is comprised of seven nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases/adenosine diphosphate (ADP) ribosyl transferases whose activities are associated with aging and cancer. In this study, we determined whether a cytoplasmic member of SIRTs, SIRT2, influences the expression of oncogenic FOXM1 in colon cancer in vitro. The association of SIRT2 and FOXM1 were analyzed using SIRT2 knockout mouse embryonic fibroblasts and SIRT2 knocked-down and overexpressing HCT116 colon cancer cell lines. Cell lines were treated with 10 ng/mL transforming growth factor-beta (TGFR) for 24 h. SIRT2 could downregulate FOXM1 through the TGF? mitogen-activated protein kinase (RAF-MEK-ERK) signaling pathway in genetically altered mouse embryonic fibroblasts and colon cancer cell lines. The indirect association between SIRT2 and FOXM1 through TGF? may be important because activators or inhibitors of SIRT2 could provide a potential approach to downregulate FOXM1 in gastrointestinal cancers.

Highlights

Transcription factor forkhead box protein M1 (FOXM1), one of the members of the forkhead family of proteins, plays a role in the progression of the cell cycle and in the regulation of cell division rate [1,2]
We tested if TGFβ exposure changes the activity of mitogenactivated protein kinase (MEK) enzyme, and alters the phosphorylation of ERK1/2 among Sirtuin 2 (SIRT2)+/+, SIRT2-/- Mouse embryonic fibroblasts (MEFs), and SIRT2 overexpressing MEFs
As with MEFs, SIRT2 knockdown in HCT116 colon cancer cells increased the phosphorylation of ERK1/2 in response to 10 ng/mL TGFβ for 4 h and strongly for 24 h (Fig. 1B)

Summary

Introduction

Transcription factor forkhead box protein M1 (FOXM1), one of the members of the forkhead family of proteins, plays a role in the progression of the cell cycle and in the regulation of cell division rate [1,2]. FOXM1 performs this role by binding to promoters of the target genes that are involved predominantly in cell division in actively proliferating cells, including in the small intestine, colon, thymus, testis and ovarian tissues [3,4]. Excessive protein expression of FOXM1 has been associated with a poor clinical prognosis and it is considered a “proto-oncogenic” transcription factor and a tumor marker [14]. In addition to continuous proliferation, oncogenic FOXM1 can FOXM1 transcriptional activity can be regulated through its posttranslational modifications, including phosphorylation, acetylation, SUMOylation, methylation and ubiquitination [18]. The transcriptional activity of FOXM1 is repressed by ubiquitination while phosphorylation of FOXM1 through the mitogenactivated protein kinase (RAF/MEK/MAPK) pathway enhances its nuclear translocation and thereby its transcriptional activity during G2/M phases [19]

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