Fat mass and obesity associated (FTO)-mediated N6-methyladenosine modification of Krüppel-like factor 3 (KLF3) promotes osteosarcoma progression

Abstract

ARSTRACT N6-methyladenosine (m6A) methylation is the most common and abundant methylation modification of eukaryotic mRNAs, which is involved in tumor initiation and progression. The study aims to explore the potential role and the regulatory mechanism of fat mass and obesity associated (FTO) in osteosarcoma (OS) progression. In this study, we detected the expressions of Krüppel-like factor 3 (KLF3) in OS cells and tissues and found that the mRNA and protein levels of KLF3 were increased in OS cells and tissues and significantly related to tumor size, metastasis, and TNM stage and poor prognosis of OS patients. FTO promoted the proliferation and invasion and suppressed apoptosis of OS cells through cell experiments in vitro. Further mechanism dissection revealed that FTO and YTHDF2 enforced the decay of KLF3 mRNA and decreased its expression. FTO-mediated mRNA demethylation inhibited KLF3 expression in the YTHDF2-dependent manner. Moreover, KLF3 overexpression abrogated FTO-induced oncogenic effects on the proliferation and invasion of OS cells. Overall, our findings showed that FTO-mediated m6A modification of KLF3 promoted OS progression, which may provide a therapeutic target for OS.

KLF transcription factors in bone diseases

“…Numerous significant signal pathways, including NF‐kB, Notch, Wnt, TGF‐β and Runx2, can be impacted by the imbalance of KLFs 21–24 . Moreover, KLFs may also be employed as noncoding RNAs (ncRNAs) target genes to regulate OS cell proliferation, invasion and migration 25,26 . Here, we highlight the role of KLFs in bone diseases and discuss the shared molecular mechanism between them by analysing previously published findings.…”

“…26,205 Overexpression of KLF3 up-regulates p21 in OS cells and counteracts the rise in Cyclin D1 expression mediated by RNA demethylase (FTO), which prevents OS cells from proliferating and invading and instead encourages apoptosis. 26 Interestingly, KLF6 also inhibits OS by affecting the cell cycle. Zhu et al 206 found that overexpression of KLF6 up-regulated the expression of p21 in MG63 cells (human OS cells) while decreasing the expression of bcl-2 and MMP-9.…”

“…Knockdown of KLF2 increased cell viability in U2OS cells (human OS cells), and conversely, high expression of KLF2 exerted pro‐apoptotic effects and inhibited proliferation through activation of cell cycle inhibitory genes p15 and p21 208 . Similar to KLF2, KLF3 impacts the cell cycle and is only weakly expressed in human soft tissue sarcomas and OS tissues 26,205 . Overexpression of KLF3 up‐regulates p21 in OS cells and counteracts the rise in Cyclin D1 expression mediated by RNA demethylase (FTO), which prevents OS cells from proliferating and invading and instead encourages apoptosis 26 .…”

Krüppel-like factors in tumors: Key regulators and therapeutic avenues

“…KLFs indirectly affect EMT in cancer tissues by regulating MMP9, TWIST, and other factors or interacting with TGF-β, WNT, and other pathways. Overexpression of KLF3 abrogates fat mass and obesity-associated-induced osteosarcoma cell invasion ( 155 ) while silencing this factor promotes EMT and metastasis in lung cancer. KLF4 has a reciprocal regulatory relationship with TGF-β1 and thus affects EMT ( 84 , 87 ).…”

Molecular mechanisms of osteosarcoma metastasis and possible treatment opportunities

“…RNA modifications also play a role in osteosarcoma metastasis. The m6A demethylase FTO mediates mRNA demethylation, promoting the decay of KLF3 mRNA and decreasing its expression, consequently facilitating osteosarcoma proliferation and metastasis ( 14 ). Also, the destabilizing effects of FTO on DACT1 mRNA promotes Wnt signaling and consequently osteosarcoma metastasis ( 15 ).…”