RSK4 inhibits breast cancer cell proliferation and invasion in�vitro, and is correlated with estrogen receptor upregulation in breast cancer

Abstract

Estrogen (E2) receptor (ER) upregulation has been associated with tumor progression and is the most commonly used clinical biomarker in breast cancer. X-linked ribosomal S6 kinase 4 (RSK4) is downregulated in breast cancer and may act as a tumor suppressor gene. In order to understand the association between the ER and RSK4, the present study studied the effects of RSK4 on ER-positive (ER +) breast cancer cell function, and the effects of E2 on RSK4 function and RSK4 methylation. Furthermore, the disease-free survival of patients with breast cancer with RSK4 hypermethylation/hypomethylation was investigated to establish the link between RSK4 methylation on patient prognosis. The expression levels of RSK4 were increased and RSK4 promoter methylation was decreased in ER + breast cancer tissues and cell lines compared with ER-negative breast cancer tissues and cell lines, respectively. ER expression was negatively correlated with RSK4 expression and positively associated with RSK4 methylation. In vitro overexpression of RSK4 decreased the proliferation, clone formation, migration and angiogenesis and increased apoptosis of breast cancer cells. Patients with RSK4 hypomethylation exhibited a longer disease-free survival compared with patients with RSK4 hypermethylation. E2 stimulation of breast cancer cells increased ER expression and RSK4 methylation, which was associated with decreased RSK4 expression. Furthermore, ER upregulation was proposed to be related to the decreased expression of RSK4 in ER + breast cancer. E2 signaling may therefore act upstream of RSK4 to promote cancer progression. The results obtained in the current study suggested that RSK4 inhibited breast cancer cell invasiveness and that RSK4 promoter hypomethylation may serve as a novel prognostic marker for patients with breast cancer.

MiR-548d-3p Promotes Gastric Cancer by Targeting RSK4

“…Overexpression of RSK4 in breast cancer cells reduces the proliferation, migration, and angiogenesis, and increases apoptosis. 43 Compared with patients with hypermethylation of RSK4, patients with hypomethylation of RSK4 showed longer disease-free survival, indicating that hypomethylation of the RSK4 promoter may potentially contribute novel prognostic markers of breast cancer patients. 43 In addition, overexpression of RSK4 reverses the resistance of human breast cancer cells to adriamycin through the PI3K/Akt signaling pathway.…”

“…43 Compared with patients with hypermethylation of RSK4, patients with hypomethylation of RSK4 showed longer disease-free survival, indicating that hypomethylation of the RSK4 promoter may potentially contribute novel prognostic markers of breast cancer patients. 43 In addition, overexpression of RSK4 reverses the resistance of human breast cancer cells to adriamycin through the PI3K/Akt signaling pathway. 44 The expression of RSK4 is low in non-small cell lung cancer tissues and is related to the clinical and pathological staging of nonsmall cell lung cancer.…”

An epigenomic landscape of cervical intraepithelial neoplasia and cervical cancer using single‐base resolution methylome and hydroxymethylome

“…PIP5K1α and PIP5K1A have been reported to be involved in carcinogenesis 63,64 . RPS6KA6 ( RSK4 ) is a putative tumor suppressor gene 65,66 . The RSK4 gene has also been reported as oncogenic gene in several cancers 67 .…”

“… 63 , 64 RPS6KA6 ( RSK4 ) is a putative tumor suppressor gene. 65 , 66 The RSK4 gene has also been reported as oncogenic gene in several cancers. 67 Overexpression of RSK4 positively correlates with poor prognosis in RCC and ESCC.…”

The role of the p90 ribosomal S6 kinase family in prostate cancer progression and therapy resistance

“…This is particularly relevant in PCa; despite several studies investigating the role of RSK1/2 in the disease (discussed here below), no study has investigated the roles of RSK3/4 in PCa. This is quite surprising, since in similar hormone-sensitive cancers such as BCa, RSK4 downregulation was shown to correlate with Estrogen Receptor (ERα) upregulation and cancer progression ( 46 , 47 ). Conversely, overexpression of RSK4 was shown to inhibit doxorubicin chemoresistance, proliferation and migration, and to increase apoptosis in BCa cells ( 48 ).…”