SHISA3, an antagonist of the Wnt/β-catenin signaling, is epigenetically silenced and its ectopic expression suppresses growth in breast cancer.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Epigenesis, Genetic* ; Gene Expression Regulation, Neoplastic*; Breast Neoplasms/*genetics ; Membrane Proteins/*metabolism ; Wnt Signaling Pathway/*genetics; Azacitidine/pharmacology ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Movement/genetics ; Cell Proliferation/drug effects ; Cell Proliferation/genetics ; DNA Methylation/genetics ; Female ; Humans ; Membrane Proteins/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism

Breast cancer (BC) is the foremost cause of cancer related deaths in women globally. Currently there is a scarcity of reliable biomarkers for its early stage diagnosis and theranostics monitoring. Altered DNA methylation patterns leading to the silencing of tumor suppressor genes are considered as an important mechanism underlying tumor development and progression in various cancer types, including BC. Very recently, epigenetic silencing of SHISA3, an antagonist of β-catenin, has been reported in various types of tumor. However, the role of SHISA3 in BC has not been investigated yet. Therefore, we aimed at evaluating the contribution of SHISA3 in BC causation by analyzing its expression and methylation levels in BC cell lines (MDA-MB231, MCF-7 and BT-474) and in 103 paired BC tissue samples. The SHISA3 expression and methylation status was determined by qPCR and methylation specific PCR (MSP) respectively. The role of SHISA3 in BC tumorigenesis was evaluated by proliferation and migration assays after ectopic expression of SHISA3. The association between SHISA3 hypermethylation and clinicopathological parameters of BC patients was also studied. The downregulation of SHISA3 expression was found in three BC cell lines used and in all BC tissue samples. However, SHISA3 promoter region was hypermethylated in 61% (63/103) tumorous tissues in comparison to the 18% of their matched normal tissues. The 5-aza-2'-deoxycytidine treatment restored SHISA3 expression by reversing promoter hypermethylation in both MDA-MB231 and MCF-7 cells. Furthermore, ectopic expression of SHISA3 significantly reduced the proliferation and migration ability of these cells. Taken together, our findings for the first time reveal epigenetic silencing and tumor suppressing role of SHISA3 in BC. Henceforth, this study has identified SHISA3 as potentially powerful target for the development of new therapies against BC, as well as novel diagnostic and therapy response monitoring approaches.
Competing Interests: The authors declare that there are no conflicts of interest.

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0 (Membrane Proteins)
0 (RNA, Messenger)
0 (SHISA3 protein, human)
M801H13NRU (Azacitidine)

Date Created: 20200722 Date Completed: 20200922 Latest Revision: 20200922

20240104

PMC7373276

10.1371/journal.pone.0236192

32692756