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Published on: July 17, 2020
TPM2 attenuates progression of prostate cancer by blocking PDLIM7-mediated nuclear translocation of YAP1
Zonglong Wu1, Liyuan Ge1, Lulin Ma1
1Department of Urology, Peking University Third Hospital, Beijing, 100191, People's Republic of China.
Background:
Prostate cancer (PCa) is a common malignant tumor of the genitourinary system. Clinical intervention in advanced PCa remains challenging. Tropomyosins 2 (TPM2) are actin-binding proteins and have been found as a biomarker candidate for certain cancers. However, no studies have explored the role of TPM2 in PCa and its regulatory mechanism.
Methods:
TPM2 expression was assessed in Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) PCa patient dataset. The effect of TPM2 on PCa progression was assessed in vitro and in vivo by quantifying proliferation, migration, invasion and tumor growth assays, and the mechanism of TPM2 in PCa progression was gradually revealed by Western blotting, immunoprecipitation, and immunofluorescence staining arrays.
Results:
TPM2 was found to be severely downregulated in tumor tissues of PCa patients compared with tumor-adjacent normal tissues. In vitro experiments revealed that TPM2 overexpression inhibited PCa cell proliferation, invasion and androgen-independent proliferation. Moreover, TPM2 overexpression inhibited the growth of subcutaneous xenograft tumors in vivo. Mechanistically, this effect was noted to be dependent on PDZ-binding motif of TPM2. TPM2 competed with YAP1 for binding to PDLIM7 through the PDZ-binding motif. The binding of TPM2 to PDLIM7 subsequently inhibited the nuclear transport function of PDLIM7 for YAP1. YAP1 sequestered in the cytoplasm phosphorylated at S127, resulting in its inactivation or degradation which in turn inhibited the expression of YAP1 downstream target genes.
Conclusions:
This study investigated the role of TPM2, PDLIM7, and YAP1 in PCa progression and castration resistance. TPM2 attenuates progression of PCa by blocking PDLIM7-mediated nuclear translocation of YAP1. Accordingly, targeting the expression or functional modulation of TPM2, PDLIM7, or YAP1 has the potential to be an effective therapeutic approach to reduce PCa proliferation and prevent the progression of castration-resistant prostate cancer (CRPC).
Insights
Tropomyosin 2 (TPM2) is downregulated in prostate cancer (PCa). TPM2 inhibits PCa progression by blocking YAP1 nuclear transport, offering a potential therapeutic target for advanced and castration-resistant PCa.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Prostate cancer (PCa) presents significant clinical challenges in advanced stages.
- Tropomyosins 2 (TPM2), actin-binding proteins, are potential biomarkers in various cancers.
- The role and regulatory mechanisms of TPM2 in PCa remain unexplored.
Purpose of the Study:
- To investigate the role of TPM2 in prostate cancer progression.
- To elucidate the underlying molecular mechanisms of TPM2 action in PCa.
- To explore the therapeutic potential of targeting TPM2, PDLIM7, and YAP1 in PCa.
Main Methods:
- TPM2 expression analysis using Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets.
- In vitro and in vivo assays to assess TPM2's effect on PCa cell proliferation, migration, invasion, and tumor growth.
- Molecular mechanism investigation using Western blotting, immunoprecipitation, and immunofluorescence.
Main Results:
- TPM2 is significantly downregulated in PCa tumor tissues compared to adjacent normal tissues.
- TPM2 overexpression inhibits PCa cell proliferation, invasion, and androgen-independent growth, both in vitro and in vivo.
- TPM2 inhibits PCa progression by competing with YAP1 for PDLIM7 binding, preventing YAP1 nuclear translocation and subsequent target gene expression.
Conclusions:
- TPM2 attenuates PCa progression by inhibiting PDLIM7-mediated nuclear translocation of YAP1.
- Targeting TPM2, PDLIM7, or YAP1 presents a potential therapeutic strategy for PCa.
- Modulating these factors may reduce PCa proliferation and prevent castration-resistant prostate cancer (CRPC) progression.
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