ABSTRACT
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).