Cell division cycle 34 is highly expressed in hepatitis C virus-positive hepatocellular carcinoma with favorable phenotypes

Takagi, Keiko; Takayama, Tadatoshi; Midorikawa, Yutaka; Hasegawa, Hiromasa; Ochiai, Takanaga; Moriguchi, Masamichi; Higaki, Tokio; Soma, Masayoshi; Nagase, Hiroki; Fujiwara, Kyoko

doi:10.3892/br.2017.912

Cited by 3 publications

(2 citation statements)

References 25 publications

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“…1). Previous studies showed that CDC34 was overexpressed in acute lymphoblastic leukemia 49 , multiple myeloma 50 , breast cancer 51 , hepatocellular carcinomas 52,53 , and prostate cancer 54 . Therefore, the mechanisms of CDC34 in promoting the initiation and progression of malignant neoplasms warrant further investigation.…”

Section: Discussionmentioning

confidence: 98%

Genome-wide identification of CDC34 that stabilizes EGFR and promotes lung carcinogenesis

Zhao

Wang

Zhou

et al. 2018

Preprint

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To systematically identify ubiquitin pathway genes that are critical to lung carcinogenesis, we used a genome-wide silencing method in this study to knockdown 696 genes in non-small cell lung cancer (NSCLC) cells. We identified 31 candidates that were required for cell proliferation in two NSCLC lines, among which the E2 ubiquitin conjugase CDC34 represented the most significant one. CDC34 was elevated in tumor tissues in 67 of 102 (65.7%) NSCLCs, and smokers had higher CDC34 than nonsmokers. The expression of CDC34 was inversely associated with overall survival of the patients. Forced expression of CDC34 promoted, whereas knockdown of CDC34 inhibited lung cancer in vitro and in vivo. CDC34 bound EGFR and competed with E3 ligase c-Cbl to inhibit the polyubiquitination and subsequent degradation of EGFR. In EGFR-L858R and EGFR-T790M/Del(exon 19)-driven lung cancer in mice, knockdown of CDC34 by lentivirus mediated transfection of short hairpin RNA significantly inhibited tumor formation. These results demonstrate that an E2 enzyme is capable of competing with E3 ligase to inhibit ubiquitination and subsequent degradation of oncoprotein substrate, and CDC34 represents an attractive therapeutic target for NSCLCs with or without drug-resistant EGFR mutations.not peer-reviewed)

show abstract

Section: Discussionmentioning

confidence: 98%

Genome-wide identification of CDC34 that stabilizes EGFR and promotes lung carcinogenesis

Zhao

Wang

Zhou

et al. 2018

Preprint

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“…1). CDC34 was overexpressed in acute lymphoblastic leukemia [42], multiple myeloma [43], breast cancer [44], hepatocellular carcinomas [45,46], and prostate cancer [47], indicating that this E2 conjugase palys a critical role in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Systematic identification of CDC34 that functions to stabilize EGFR and promote lung carcinogenesis

et al. 2020

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Background: How the oncoprotein epidermal growth factor receptor (EGFR) evades proteolytic degradation and accumulates in non-small cell lung cancer (NSCLC) remains unclear, and ubiquitin pathway genes (UPGs) that are critical to NSCLC needs to be systematically identified. Methods: A total of 696 UPGs (including E1, E2, E3, and deubiquitinases) were silenced by small interfering RNA (siRNA) library in NSCLC cells, the candidates were verified, and their significance was evaluated in patients with NSCLC. The effects of a candidate gene on EGFR were investigated in vitro and in vivo. Findings: We report 31 candidates that are required for cell proliferation, with the E2 ubiquitin conjugase CDC34 as the most significant one. CDC34 is elevated in tumor tissues in 76 of 114 (66.7%) NSCLCs and inversely associated with prognosis, is higher in smoker patients than nonsmoker patients, and is induced by tobacco carcinogens in normal human lung epithelial cells. Forced expression of CDC34 promotes, whereas knockdown of CDC34 inhibits, NSCLC cell proliferation in vitro and in vivo. CDC34 competes with c-Cbl to bind Y1045 to inhibit polyubiquitination and degradation of EGFR. In EGFR-L858R and EGFR-T790M/Del (exon 19)driven lung tumor growth in mouse models, knockdown of CDC34 significantly inhibits tumor formation. Interpretation: These results demonstrate that an E2 enzyme is capable of competing with E3 ligase to stabilize substrates, and CDC34 represents an attractive therapeutic target for NSCLCs.

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Structural insights into E1 recognition and the ubiquitin-conjugating activity of the E2 enzyme Cdc34

et al. 2019

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Ubiquitin (Ub) signaling requires the sequential interactions and activities of three enzymes, E1, E2, and E3. Cdc34 is an E2 that plays a key role in regulating cell cycle progression and requires unique structural elements to function. The molecular basis by which Cdc34 engages its E1 and the structural mechanisms by which its unique C-terminal extension functions in Cdc34 activity are unknown. Here, we present crystal structures of Cdc34 alone and in complex with E1, and a Cdc34~Ub thioester mimetic that represents the product of Uba1-Cdc34 Ub transthiolation. These structures reveal conformational changes in Uba1 and Cdc34 and a unique binding mode that are required for transthiolation. The Cdc34~Ub structure reveals contacts between the Cdc34 C-terminal extension and Ub that stabilize Cdc34~Ub in a closed conformation and are critical for Ub discharge. Altogether, our structural, biochemical, and cell-based studies provide insights into the molecular mechanisms by which Cdc34 function in cells.

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Cell division cycle 34 is highly expressed in hepatitis C virus-positive hepatocellular carcinoma with favorable phenotypes

Cited by 3 publications

References 25 publications

Genome-wide identification of CDC34 that stabilizes EGFR and promotes lung carcinogenesis

Genome-wide identification of CDC34 that stabilizes EGFR and promotes lung carcinogenesis

Systematic identification of CDC34 that functions to stabilize EGFR and promote lung carcinogenesis

Structural insights into E1 recognition and the ubiquitin-conjugating activity of the E2 enzyme Cdc34

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