Abstract
BackgroundBreast cancer ranks No. 1 in women cancer incidence, while triple negative breast cancer (TNBC) is the most aggressive and the worst prognostic subtype in all breast cancer subtypes. Compared with estrogen receptor alpha positive breast cancer, which could be well controlled by endocrine therapy, TNBC is lack of mature molecular targets for medical therapy. Thus, it is urgent and necessary to discovery the carcinogenic mechanism and potential therapeutic targets for TNBC. Recent studies reveal that Hippo/YAP signaling is an important mediator for TNBC progression. Our current study investigates the role of RING finger protein RNF181 in modulation Hippo/YAP signaling.MethodsYAP and RN181 protein level were measured by western blot, while the Hippo classical target genes were measured by real-time PCR. WST1 assay were used to measure cell proliferation, the trans-well and wound healing were used to measure the cell migration and invasion capacity. Protein stability and ubiquitin assay were used to detect the YAP protein ubiquitin and stability. The immuno-precipitation assays were used to detect the protein interactions. Immuno-staining was used to detect the protein localization of YAP and RNF181, while the ubiquitin-based immuno-precipitation assays were used to detect the specific ubiquitination manner of YAP.ResultsOur current study identified a novel modulator-RNF181 as a positive mediator for Hippo/YAP signaling activation in TNBC. RNF181 depletion significantly inhibited TNBC cell migration, invasion and proliferation, which effect could be rescued by YAP overexpression. RNF181 depletion decreased YAP protein level and Hippo signaling target genes, such as CTGF and CYR61, in TNBC cell lines. Immuno-precipitation assay showed that RNF181 interact with YAP and promoted YAP stability by inhibition K48-linked poly-ubiquitination of YAP in TNBC cells. Besides, public available data showed that RNF181 is elevated in breast cancer and related to poor prognosis in TNBC patients.ConclusionOur study provides evidence to establish a non-proteolytic mechanism in modulating Hippo signaling in breast cancer. RNF181 could be an interesting marker for triple negative breast cancer prognostics and therapeutics.
Highlights
Breast cancer ranks No 1 in women cancer incidence, while triple negative breast cancer (TNBC) is the most aggressive and the worst prognostic subtype in all breast cancer subtypes
Ring finger protein 181 (RNF181) controls Hippo signaling in triple negative breast cancer via modulating Yes-associated protein (YAP) stability and ubiquitination level
From the Oncomine database, we find that RNF181 is elevated in breast cancer, compared with normal breast tissue in multiple cohorts (Fig. 1a–c)
Summary
Breast cancer ranks No 1 in women cancer incidence, while triple negative breast cancer (TNBC) is the most aggressive and the worst prognostic subtype in all breast cancer subtypes. TNBC has higher trend to metastasize and poorer overall survival compared with other breast cancer subtypes [3]. Since it is lack of therapeutic targets in TNBC, it is urgent to uncover the oncogenic mechanism and novel targeted therapies for TNBC patients. The organ hemostasis is dependent on an internal balance among proliferation, apoptosis, stem cell selfrenewal and differentiation [4] These processes are necessary for the tissue hemostasis, while the deviation of such regulation leads development failure or carcinogenesis. While Hippo signaling is shuttled down, unphosphorylated YAP/TAZ could translocate into the nuclear and associate with several transcriptional factors, including TEADs [6]. YAP/TAZ are important effectors for Hippo pathway, which could shuttle between cytosol and nuclear
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