DBC1/CCAR2 is involved in the stabilization of androgen receptor and the progression of osteosarcoma

Wagle, Sajeev; Park, See‐Hyoung; Kim, Kyoung Min; Moon, Young Jae; Bae, Jong Seok; Kwon, Keun Sang; Park, Ho Sung; Lee, Ho; Moon, Woo Sung; Kim, Jung Ryul; Jang, Kyu Yun

doi:10.1038/srep13144

Cited by 36 publications

(36 citation statements)

References 37 publications

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“…Both CDK11 and AR expression showed adverse predictive value for osteosarcoma patients in disease free survival rates. Consistent with these results, while this manuscript was in preparation, another study also demonstrated that AR expression is abundant osteosarcoma and AR is an independent prognostic indicator of overall survival and relapse-free survival in patients33. The prognostic value of AR has also been reported in prostate cancer.…”

Section: Discussionsupporting

confidence: 77%

Androgen receptor is a potential novel prognostic marker and oncogenic target in osteosarcoma with dependence on CDK11

Liao

Sassi

Halvorsen

et al. 2017

Sci Rep

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Osteosarcoma is the most common bone cancer in children and adolescents. Previously, we have found that cyclin-dependent kinase 11 (CDK11) signaling was essential for osteosarcoma cell growth and survival. Subsequently, CDK11 siRNA gene targeting, expression profiling, and network reconstruction of differentially expressed genes were performed between CDK11 knock down and wild type osteosarcoma cells. Reconstructed network of the differentially expressed genes pointed to the AR as key to CDK11 signaling in osteosarcoma. CDK11 increased transcriptional activation of AR gene in osteosarcoma cell lines. AR protein was highly expressed in various osteosarcoma cell lines and patient tumor tissues. Tissue microarray analysis showed that the disease-free survival rate for patients with high-expression of AR was significantly shorter than for patients with low-expression of AR. In addition, AR gene expression knockdown via siRNA greatly inhibited cell growth and viability. Similar results were found in osteosarcoma cells treated with AR inhibitor. These findings suggest that CDK11 is involved in the regulation of AR pathway and AR can be a potential novel prognostic marker and therapeutic target for osteosarcoma treatment.

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Section: Discussionsupporting

confidence: 77%

Androgen receptor is a potential novel prognostic marker and oncogenic target in osteosarcoma with dependence on CDK11

Liao

Sassi

Halvorsen

et al. 2017

Sci Rep

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“…There have been many studies on DBC1 in human malignant tumors demonstrating its function in breast cancer . Previous studies have shown the nuclear expression of DBC1 is positively related to clinicopathological factors and poor prognosis in patients with breast cancer .…”

Section: Introductionmentioning

confidence: 99%

ZNF326 promotes a malignant phenotype of breast cancer by interacting with DBC1

Wang

Han

et al. 2018

Molecular Carcinogenesis

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The biological role and underlying mechanism of action of zinc-finger protein 326 (ZNF326) in malignant tumors, including breast cancer, are still not clear. In this study, we detected high expression of ZNF326 in breast cancer specimens (60/111, 54.1%) and breast cancer cell lines (7/7); the expression level of ZNF326 was inversely associated with advanced pTNM stage (P = 0.002), positive lymph node metastasis (P = 0.004), poor prognosis in patients with breast cancer (P = 0.0097), and ER/PR/Her2 status (P = 0.013). Meanwhile, the ectopic expression of ZNF326 significantly upregulated MMP7, EMT-related proteins (Snail and Slug), and cell cycle-related proteins (cyclinA2 and cyclinB1); downregulated E-cadherin expression; and promoted the proliferation and invasiveness of breast cancer cells both in vivo and in vitro. Mechanistically, co-immunoprecipitation and immunofluorescence assays both demonstrated that ZNF326 interacted with deleted in breast cancer-1 (DBC1) in breast cancer cells. Additionally, DBC1 knockdown eliminated the up-regulation of MMP7, EMT-related proteins, and cell cycle-related proteins as well as the enhanced proliferation and invasiveness induced by ZNF326. Therefore, we concluded that ZNF326 is highly expressed in breast cancer, is associated with poor prognosis, and plays a vital role in promoting the malignant phenotype of breast cancer cells by interacting with DBC1.

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“…Originally named DBC1 by mistake because its gene maps to a region of chromosome 8 that was found homozygously deleted in breast cancers, 1 CCAR2 was instead upregulated in many types of tumors. 1 These findings, together with the fact that CCAR2 loss in vitro prevents cancer cells growth 6, 7 suggested for this protein a role of tumor promoter. On the other hand, CCAR2-knockout mice are tumor prone 8 and, intriguingly, in some cancer patients, CCAR2 down-regulation is associated with poor prognosis, 1 suggesting that it acts as tumor suppressor.…”

mentioning

confidence: 99%

A novel crosstalk between CCAR2 and AKT pathway in the regulation of cancer cell proliferation

et al. 2016

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Human CCAR2 has recently emerged as having a pivotal role in the DNA damage response, promoting apoptosis and repair of heterochromatic DNA breaks. However, less is known about the function of CCAR2 in tumor formation and cancer progression. Here, we demonstrate, for the first time, that CCAR2 loss inhibits the proliferation of cancer cells, but preserves the growth of normal cells. Investigating the mechanisms responsible for this differential effect, we found that CCAR2 depletion specifically impairs the activation of AKT pathway in cancer cells, but not in normal cells, by reducing AKT phosphorylation on Ser473. This effect is achieved through the transcriptional upregulation of TRB3 gene and accumulation of TRB3 protein, which then binds to and inhibits the phosphorylation and activation of AKT. The defective activation of AKT finally results in reduced GSK3β phosphorylation, prevention of G1/S transition and inhibition of cancer cell growth. These results establish an important role for CCAR2 in cancer cells proliferation and could shed new light on novel therapeutic strategies against cancer, devoid of detrimental side effects.

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DBC1/CCAR2 is involved in the stabilization of androgen receptor and the progression of osteosarcoma

Cited by 36 publications

References 37 publications

Androgen receptor is a potential novel prognostic marker and oncogenic target in osteosarcoma with dependence on CDK11

Androgen receptor is a potential novel prognostic marker and oncogenic target in osteosarcoma with dependence on CDK11

ZNF326 promotes a malignant phenotype of breast cancer by interacting with DBC1

A novel crosstalk between CCAR2 and AKT pathway in the regulation of cancer cell proliferation

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