HIPK2 downregulates vimentin and inhibits breast cancer cell invasion

Abstract

Vimentin, a mesenchymal marker, is frequently overexpressed in epithelial carcinomas undergoing epithelial to mesenchymal transition (EMT), a condition correlated with invasiveness and poor prognosis. Therefore, vimentin is a potential molecular target for anticancer therapy. Emerging studies in experimental models underscore the functions of homeodomain-interacting protein kinase 2 (HIPK2) as potential oncosuppressor by acting as transcriptional corepressor or catalytic activator of molecules involved in apoptosis and response to antitumor drugs. However, an involvement of HIPK2 in limiting tumor invasion remains to be elucidated. This study, by starting with a microarray analysis, demonstrates that HIPK2 downregulates vimentin expression in invasive, vimentin-positive, MDA-MB-231 breast cancer cells and in the noninvasive MCF7 breast cancer cells subjected to chemical hypoxia, a drive for mesenchymal shift and tumor invasion. At functional level, vimentin downregulation by HIPK2 correlates with inhibition of breast tumor cell invasion. Together, these data show that vimentin is a novel target for HIPK2 repressor function and that HIPK2-mediated vimentin downregulation can contribute to inhibition of breast cancer cells invasion that might be applied in clinical therapy.

HIPK2 inhibits cell metastasis and improves chemosensitivity in esophageal squamous cell carcinoma

“…This result is consistent with previous studies, in which HIPK2 downregulation has been reported in bladder cancer, breast cancer and ovarian cancer (12,14,22). HIPK2 overexpression has also been demonstrated in patients with cervical and colorectal cancer with familial adenomatous polyposis (23,24).…”

“…Chung et al (29) previously reported that N-cadherin suppresses RAC-γ serine/threonine-protein kinase to promote cell motility in mammary tumor cells. Furthermore, Qian et al (30) demonstrated that N-cadherin served a pivotal role in promoting metastasis through the regulation of extracellular-regulated kinase and protein kinase B. Nodale et al (14) demonstrated that MDA-MB-231 cells transfected with HIPK2 had decreased levels of vimentin mRNA that strongly correlated with re-expression of E-cadherin, which is indicative of a reversion of the EMT phenotype. Tan et al (15) also demonstrated that HIPK2 knockdown increased the levels of the mesenchymal markers N-cadherin and fibronectin and decreased the level of E-cadherin, indicating that EMT is induced by HIPK2 downregulation.…”

“…Puca et al (12) demonstrated that HIPK2 is an important regulator of p53 activity in response to chemotherapeutic agent cisplatin and Lazzari et al (13) indicated that HIPK2 knockdown induces resistance to multiple anticancer agents, including doxorubicin and cisplatin. HIPK2-mediated vimentin downregulation may contribute to the inhibition of breast cancer cell invasion (14). In bladder cancer, HIPK2 inhibition promotes EMT and subsequent cell invasion, at least in part by activating Wnt signaling (15).…”

Tumor suppressive role for kinases phosphorylating p53 in DNA damage‐induced apoptosis

“…HIPK2 was required for the Fbw7‐dependent proteasomal degradation of Notch1 by phosphorylating its intracellular domain, suggesting that HIPK2 regulates tumor progression . Additionally, vimentin downregulation by HIPK2 correlated with inhibition of breast tumor cell invasion . In heterozygous p53 ‐deficient background, mice with heterozygous loss of HIPK2 gene developed more lymphomas after irradiation than those with wild‐type HIPK2 gene .…”

“…67 Additionally, vimentin downregulation by HIPK2 correlated with inhibition of breast tumor cell invasion. 68 In heterozygous p53-deficient background, mice with heterozygous loss of HIPK2 gene developed more lymphomas after irradiation than those with wild-type HIPK2 gene. 69 These findings indicate that HIPK2 is a promising target for cancer treatment.…”