Colorectal cancer (CRC) is one of the most common cancers, ranking third in morbidity and tumor-related mortality among both men and women worldwide. Moreover, approximately 20% of CRC patients have metastases at the time of diagnosis [
1]. Metastasis is the leading cause of death among CRC patients [
2]. Although systemic treatment of metastatic CRC has improved, the 5-year survival rate is only 12–14%, and because of this poor prognosis, understanding the underlying mechanism of the metastatic process in CRC is critical for both early detection of metastases and more effective treatment [
3].
The gene cAMP responsive element binding protein 5 (CREB5), which is located on chromosome 7 (7p15.1), encodes a transcription activator in eukaryotic cells [
4]. CREB5 belongs to the ATF/CREB family, the members of which are characterized by a high affinity for cAMP-response elements (CREs) [
5]. The targets of the ATF/CREB family include transcriptional regulators (including chromatin-modifying enzymes, coactivators, and corepressors), genes involved in mitochondrial homeostasis and protein import, and genes associated with proliferation and cell cycle entry, metabolism, proteases, transporters, and chaperones [
6]. As an ATF/CREB family member, the CREB5 protein contains several important functional domains, including N-terminal zinc finger and C-terminal bZIP domains, the latter of which includes a DNA binding region and leucine zipper [
7]. CREB5 is a transcription factor that specifically binds to CRE as a homodimer or a heterodimer with c-Jun or CRE-BP1 and functions as a CRE-dependent trans-activator [
8]. CREB5 is physiologically required for embryonic development in mice [
9]. Recent studies revealed the roles of CREB5 in the development and progression of cancers. Examination of TCGA pan cancer datasets revealed frequent CREB5 amplification and overexpression in kidney cancers, sarcomas, lymphomas, and lung adenocarcinomas as well as glioblastomas and gliomas [
10]. Experimental investigations showed that CREB5 was upregulated in ovarian cancers [
11], hepatocellular carcinoma [
12], and prostate cancer [
10]. High CREB5 expression correlated with a poor prognosis in epithelial ovarian cancer [
11] and hepatocellular carcinoma [
12]. CREB5 overexpression increased the proliferation of hepatocellular carcinoma [
12]. Moreover, overexpression or amplification of CREB5 promoted proliferation and mediated resistance to AR inhibition in metastatic castration-resistant prostate cancers [
10]. In silico analysis showed that the CREB5 regulatory network was involved in CRC metastasis [
13]. In addition, qRT-PCR assay revealed that CREB5 mRNA was upregulated in CRC tissues and cells [
14]. In vitro assays revealed that overexpression of CREB5 resulted in enhanced proliferation and migration and apoptosis inhibition in CRC cells [
14]. These findings suggest that CREB5 may play an essential role in the progression of CRC. However, the specific function and molecular mechanism of CREB5 in CRC metastasis remain largely unclear.
Activation of the HGF/MET signalling pathway has been reported to lead to the occurrence and metastasis of a variety of tumors, including CRC, breast cancer, ovarian cancer, lung cancer, and liver cancer [
15]. As a tyrosine kinase receptor, MET can be activated by dimerization, multimerization, and phosphorylation after binding to its ligand hepatocyte growth factor (HGF) [
16]. Activation of HGF/MET can initiate downstream signalling pathways that drive malignant progression in many types of tumors. MET is considered an essential factor for early invasion and metastasis of CRC and can be regarded as an important prognostic indicator [
17,
18]. In the present study, we found that CREB5 promotes CRC invasion and metastasis by increasing MET expression to activate HGF-MET signalling. These results uncover a new molecular mechanism for cancer metastasis and suggest that CREB5 may be a promising target for CRC treatment.