Claudin-3 Loss of Expression Is a Prognostic Marker in Castration-Resistant Prostate Cancer

Castration-resistant prostate cancer (CRPC) development is the foremost concern after treatment of patients with high risk with locally advanced or metastatic prostate cancer. Androgen receptor (AR) is the main driver of CRPC development, through its interaction with epigenetic modifier genes, placing epigenetics modifications in the forefront of CRPC development. Comparing the DNA methylation and expression profile of androgen-sensitive and -refractory prostate cancer cells, we describe the epigenetic silencing of claudin-3 (CLDN3) in AR positive cells resistant to androgen deprivation (LNCaP-abl). CLDN3 silencing was associated with DNA methylation, loss of histone acetylation and H3K27 methylation, and was re-expressed by the combined treatment with the epigenetic modulators Aza and SAHA. From a functional point of view, CLDN3 loss was associated with increased cellular invasion. Immunohistochemical analysis showed decreased CLDN3 expression in samples from CRPC patients. Interestingly, CLDN3 expression was significantly decreased in samples from patients with high total Gleason score (>= 8) and locally advanced tumors. Finally, CLDN3 loss of expression was associated with worse disease-free survival and time to clinical progression. In conclusion, our findings strongly indicate that epigenetic silencing of CLDN3 is a common event in CRPC that could be useful as a molecular marker for the prognosis of prostate cancer patients and to discriminate aggressive from indolent prostate tumors.

Automated summary

The development of castration-resistant prostate cancer (CRPC) is a major concern in high-risk patients after treatment for locally advanced or metastatic prostate cancer. Androgen receptor (AR) is implicated in CRPC development through its interaction with epigenetic modifier genes, highlighting the significance of epigenetic modifications. Our study reveals the epigenetic silencing of claudin-3 (CLDN3) in AR-positive CRPC cells, which is associated with DNA methylation, histone acetylation loss, and H3K27 methylation. CLDN3 expression can be restored by combined treatment with epigenetic modulators. Additionally, decreased CLDN3 expression is observed in CRPC patient samples, particularly in patients with high Gleason scores and locally advanced tumors. CLDN3 loss is also linked to worse disease-free survival and time to clinical progression, suggesting its potential as a molecular marker for prognosis and distinguishing aggressive from indolent prostate tumors.