NSD2 inhibition suppresses metastasis in cervical cancer by promoting TGF-β/TGF-βRI/SMADs signaling

Abstract

The molecular mechanisms revealing cervical cancer progression remain unclear. NSD2 belongs to the NSD family of histone lysine methyltransferases (HMTases), and is a histone methyltransferase that regulates dimethylation of histone 3 lysine 36 (H3K36me2). In this study, we explored the effects of NSD2 on the tumorigenesis and metastasis in cervical cancer. We found that NSD2 exhibited a pattern of gradual up-regulation from normal cervix (NC) to cervical carcinoma in situ (CIS) and then to invasive cervical cancer (ICC). NSD2 knockdown markedly reduced the cervical cancer cell proliferation. Loss of function assay in vitro suggested that NSD2 deletion markedly prevented the cervical cancer cell migration and invasion. Consistently, the in vivo results demonstrated that NSD2 knockdown not only reduced tumor growth, but also prevented the development of tumor metastasis. In addition, NSD2 knockdown clearly reduced the expression levels of transforming growth factor-β1 (TGF-β1), TGF-βRI, phosphorylated SMAD2 and SMAD3 in cervical cancer cells, accompanied with the decreased expression of genes that promoted tumor metastasis. Importantly, we found that NSD2 knockdown-regulated expression levels of metastasis-associated genes were reversed by TGF-β1 incubation. Therefore, our findings demonstrated that NSD2-modulated activation of TGF-β1/TGF-βRI/SMADs signaling pathway was crucial for cervical cancer progression, which might be a promising therapeutic strategy to overcome metastasis in cervical cancer.