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DLEC1, a 3p tumor suppressor, represses NF-κB signaling and is methylated in prostate cancer

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Abstract

Deleted in lung and esophageal cancer 1 (DLEC1), located at 3p22-p21.3, is involved in the carcinogenesis of multiple cancers, but its role in prostate cancer (PrCa) remains unclear. Here, we studied the epigenetic alteration of DLEC1 and its functions in prostate cancer. We found that DLEC1 was highly expressed in normal prostate tissues, normal prostatic epithelium cell line (RWPE-1), and benign prostatic hyperplasia cell line (BPH-1), but frequently downregulated by promoter methylation in PrCa cell lines. Pharmacologic demethylation could restore DLEC1 expression. DLEC1 was downregulated in prostate tumor tissues compared with their adjacent non-malignant tissues. DLEC1 was methylated in 76/110 primary tumors, but rarely in benign prostatic hyperplasia tissues. DLEC1 methylation was associated with higher PSA levels (p = 0.016), higher Gleason scores (p = 0.015), and more advanced tumor stages (p = 0.003). Furthermore, DLEC1 methylation was detected in 11/30 urine sediment samples from PrCa patients, but seldom in ones from BPH patients. Ectopic expression of DLEC1 inhibited the colony formation of PrCa cells, through inducing cell apoptosis. DLEC1 also suppressed PrCa cell migration. Moreover, DLEC1 inhibited NF-κB transcription activity in PrCa and HEK293 cells. Taken together, our data demonstrate that DLEC1 functions as a tumor suppressor but is frequently methylated in prostate cancer. DLEC1 methylation is associated with prostate cancer progression, which could be a non-invasive epigenetic biomarker for PrCa diagnosis.

Key messages

• Promoter methylation of DLEC1 is a potential prognostic biomarker for PrCa.

• DLEC1, a functional tumor suppressor, is frequently methylated in PrCa.

• DLEC1 suppresses prostate cancer growth and metastatic behavior.

• DLEC1 mediates tumor-suppressive activities through NF-κB signaling.

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Abbreviations

Aza:

5-Aza-2-deoxycytidine

ATCC:

The American Type Culture Collection

BGS:

Bisulfite genomic sequence

BPH:

Benign prostatic hyperplasia

DLEC1:

Deleted in lung and esophageal cancer

DRE:

Digital rectal examination

FBS:

Fetal bovine serum

IHC:

Immunohistochemistry

MSP:

Methylation specific polymerase chain reaction

PrCa:

Prostate cancer

RT-PCR:

Reverse-transcription polymerase chain reaction

RP:

Radical prostatectomy

TSA:

Trichostatin A

TSG:

Tumor suppressor gene

TUR:

Transurethral resection

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Acknowledgments

This study was supported by grants from the National Natural Science Foundation (No. 81272290, 81171971, 81372898 and 81101492), Beijing Municipal Science and Technology Commission (No.Z131107002213130 and Z121107002512012), Central Health Care Research Foundation (No. W2013BJ28), Shenzhen city (GJHS20120702105523309), and China 973 Program (2012CB518305).

Conflicts of interest

The authors declare no conflict of interest.

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    Authors and Affiliations

    1. Department of Urology, National Research Center for Genitourinary Oncology, Peking University First Hospital and Institute of Urology, Beijing, China

      Lian Zhang, Qian Zhang, Yu Fan, Qun He, Tianjing LV, Wenke Han, Jun Li, Yang Yang, Ben Xu, Lu Wang, Qianling Liu, Yinglu Guo & Jie Jin

    2. Cancer Epigenetics Laboratory, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Shatin, Hong Kong

      LiLi Li, Zhaohui Wang & Qian Tao

    3. Department of Pathology, Cancer Institute and Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China

      Jianming Ying

    4. Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China

      Yinghao Sun

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    Correspondence to Qian Tao or Jie Jin.

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    Lian Zhang and Qian Zhang contributed equally to this work.

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    Zhang, L., Zhang, Q., Li, L. et al. DLEC1, a 3p tumor suppressor, represses NF-κB signaling and is methylated in prostate cancer. J Mol Med 93, 691–701 (2015). https://doi.org/10.1007/s00109-015-1255-5

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