SUMOylation of HSP27 by small ubiquitin-like modifier 2/3 promotes proliferation and invasion of hepatocellular carcinoma cells

Abstract

Primary hepatocellular carcinoma (PHC) is a major health problem worldwide and is one of the 10 most commonly diagnosed cancers in China. Heat shock protein 27 (HSP27) were found to be overexpressed in a wide range of malignancies including PHC, however, post-translational modification of HSP27 still needs exploration in PHC. Recently, SUMOylation, an important post-translational modification associating with the development of many kinds of cancers has been intensively studied. In the current study, mRNA and protein level of HSP27 in archived tumor samples representing various pathological characteristics of PHC were examined, and modification of HSP27 by SUMO2/3 was investigated. HSP27 were expressed abundantly in patients' tumor tissues, and found to be associated with pathological progression. Besides, HSP27 was also elevated significantly in liver cancer cell lines Huh7 and HepG2 compared with human hepatocyte cells L02. Furthermore, knockdown of HSP27 was found to be associated with the decreased proliferation and invasion ability in Huh7 and HepG2 cells. Immunofluorescence assay showed that HSP27 and SUMO2/3 were co-localized in the subcellular, and co-immunoprecipitation verified the interaction between HSP27 and SUMO2/3. Overexpression of SUMO2/3 upregulated the HSP27 protein level and promotes Huh7 and HepG2 cell proliferation and invasion, and vice versa when the SUMO2/3 was knockdown. Taken together, increased protein level of HSP27 through SUMO2/3-mediated SUMOylation plays crucial roles in the progression of PHC, and this finding may shed light on developing potential therapeutic targets for PHC.

SUMOylation of HSP27 regulates PKM2 to promote esophageal squamous cell carcinoma progression

“…From these data, it may be inferred that SUMO2/3 can prevent the HSP27 protein from degradation. These observations were in agreement with a previous study reporting that SUMO2/3 was required for the promotion of proliferation and invasion of liver cancer cells by HSP27 (21). Of note, the data of the present study strongly support that SUMOylation stabilizes HSP27 and protects it from degradation, which was also reported previously by Ge et al (21).…”

“…Liu et al (17) found that SUMO2/3 promotes the transformation of chronic hepatitis B to liver cancer by stabilizing p65 in the cytoplasm and deactivating NF-κB. Ge et al (21) reported that SUMO2/3 in HCC cells protects HSP27 from degradation by binding to the GKHE sequence on the HSP27 protein, thus promoting the motility of tumor cells. However, the SUMOylation of HSP27 has rarely been reported in ESCC.…”

“…Extensive research has confirmed that SUMOylation plays a crucial role in human diseases (20). It was recently reported that HSP27 and SUMO2/3 combine directly, which induces SUMOylation of HSP27 to accelerate the invasion and metastasis of HCC cells (21). However, it remains unclear whether there is an interaction between HSP27 and SUMO2/3 in ESCC.…”

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

“…The Hippo pathway-associated role of HSP27 has been demonstrated in various tumors, including prostate, breast, and lung cancers [21]. Sumoylation, a reversible post-translational modification by the small ubiquitin-related modifier (SUMO) plays an essential role in cancer development through the modulation of DNA damage response, cell cycle progression, metastasis, and apoptosis, accompanied by upregulation of HSP27 [22]. The increased expression of HSP27 also stimulates epidermal growth factor (EGF)-induced cell migration, invasion, and matrix metalloproteinase (MMP) activity as well as the expression of epithelial to mesenchymal transition (EMT) markers via activation or overexpression of AKT, GSK3β, and β-catenin [23].…”

Small Heat Shock Proteins in Cancers: Functions and Therapeutic Potential for Cancer Therapy

“…Initially, HspB1 was reported to promote the invasion of breast cancer cells [96] by upregulation of MMP-9 expression [97] but decrease the motility of breast cancer cells [96]. Subsequently, numerous studies have demonstrated that overexpression of HspB5 in breast cancer cells increased cell migration and invasion [28], and HspB1 silencing in colorectal [98], prostate [99], ovarian [100], and liver [101] cancers or head and neck squamous cell carcinoma [102], HspB8 silencing in breast cancer [61], or HspB5 silencing in colorectal [103] and renal [53] cancers inhibit migration and/or invasion of cancer cells. Moreover, a number of clinical data studies have shown that primary tumor expression of sHSPs is associated with aggressive tumor characteristics and tumor progression.…”