HOXB13 contributes to G1/S and G2/M checkpoint controls in prostate

Mol Cell Endocrinol. 2014 Mar 5;383(1-2):38-47. doi: 10.1016/j.mce.2013.12.003. Epub 2013 Dec 8.


HOXB13 is a homeobox protein that is expressed in normal adult prostate and colon tissues; however, its deregulated expression was evidenced in various malignancies. To characterize the putative role of HOXB13 in cell cycle progression, we performed overexpression and siRNA-mediated knockdown studies in PC-3 and LNCaP cells. Immunohistochemistry (IHC) analyses were also performed using formalin-fixed, paraffin-embedded tissues containing normal, H-PIN and PCa sections from 20 radical prostatectomy specimens. Furthermore, when the role of HOXB13 during cell cycle progression, association with cyclins, cell growth and colony formation using real-time cell proliferation were assessed, we observed that ectopic expression of HOXB13 accumulated cells at G1 through decreasing the cyclin D1 level by promoting its ubiquitination and degradation. This loss slowed S phase entry in both cell lines examined, with an associated decrease in pRb((S780) and (S795)) phosphorylations. Contrary, siRNA-mediated depletion of HOXB13 expression noticeably increased cyclin levels, stabilized E2F1 and CDC25C, subsequent to increased pRb phosphorylations. This increase in Cyclin B1 and CDC25C both together facilitated activation of cyclin B complex via dephosphorylating CDK1((T14Y15)), and resumed the G2/M transition after nocodazole synchronization. Despite an increase in the total expression level and cytoplasmic retention of HOXB13 in H-PIN and PCa samples that were observed via IHC evaluation of prostate tissues, HOXB13 depletion facilitated to an increase in PC-3 and LNCaP cell proliferation. Thus, we suggest that HOXB13 expression is required for cell cycle regulation, and increases by an unknown mechanism consequent to its functional loss in cancer.

Keywords: Cell cycle; Cyclin D1; E2F regulation; Homeobox protein; Prostate tissues; Rb phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin B1 / genetics
  • Cyclin B1 / metabolism
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism
  • G1 Phase Cell Cycle Checkpoints / genetics*
  • G2 Phase Cell Cycle Checkpoints / genetics*
  • Gene Expression Regulation, Neoplastic*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Phosphorylation
  • Prostate / metabolism
  • Prostate / pathology
  • Prostatectomy
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Proteolysis
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism
  • Signal Transduction
  • Ubiquitination
  • cdc25 Phosphatases / genetics
  • cdc25 Phosphatases / metabolism


  • Cyclin B1
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • HOXB13 protein, human
  • Homeodomain Proteins
  • Retinoblastoma Protein
  • Cyclin D1
  • CDC2 Protein Kinase
  • CDC25C protein, human
  • cdc25 Phosphatases