TUBB3 is associated with PTEN, neuroendocrine differentiation, and castration resistance in prostate cancer

Yohei Sekino, Xiangrui Han, Takashi Babasaki, Shunsuke Miyamoto, Kohei Kobatake, Hiroyuki Kitano, Kenichiro Ikeda, Keisuke Goto, Shogo Inoue, Tetsutaro Hayashi, Jun Teishima, Masaki Shiota, Yukio Takeshima, Wataru Yasui, Akio Matsubara

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Tubulin-β3 encoded by the Tubulin-β3 (TUBB3) gene is a microtubule protein. Previous studies have shown that TUBB3 expression is upregulated in castration-resistant prostate cancer (CaP) and is involved in taxane resistance. However, the biological mechanism of TUBB3 involvement in the progression to castration-resistant CaP is not fully elucidated. This study aimed to analyze the expression and function of TUBB3 in localized and metastatic CaP. Methods: TUBB3 expression was determined using immunohistochemistry in localized and metastatic CaP. We also investigated the association between TUBB3, phosphatase and tensin homolog (PTEN), and neuroendocrine differentiation and examined the involvement of TUBB3 in new antiandrogen drugs (enzalutamide and apalutamide) resistance in metastatic CaP. Results: In 155 cases of localized CaP, immunohistochemistry showed that 5 (3.2%) of the CaP cases were positive for tubulin-β3. Kaplan–Meier analysis showed that high expression of tubulin-β3 was associated with poor prostate-specific antigen recurrence-free survival after radical prostatectomy. In 57 cases of metastatic CaP, immunohistochemistry showed that 14 (25%) cases were positive for tubulin-β3. Tubulin-β3 expression was higher in metastatic CaP than in localized CaP. High tubulin-β3 expression was correlated with negative PTEN expression. TUBB3 expression was increased in neuroendocrine CaP based on several public databases. PTEN knockout decreased the sensitivity to enzalutamide and apalutamide in 22Rv-1 cells. TUBB3 knockdown reversed the sensitivity to enzalutamide and apalutamide in PTEN-CRISPR 22Rv-1 cells. High expression of tubulin-β3 and negative expression of PTEN were significantly associated with poor overall survival in metastatic CaP treated with androgen deprivation therapy. Conclusions: These results suggest that TUBB3 may be a useful predictive biomarker for survival and play an essential role in antiandrogen resistance in CaP.

Original languageEnglish
JournalUrologic Oncology: Seminars and Original Investigations
DOIs
Publication statusAccepted/In press - 2021

All Science Journal Classification (ASJC) codes

  • Oncology
  • Urology

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