Functional implication of Dclk1 and Dclk1-expressing cells in cancer

Westphalen, C. Benedikt; Quante, Michael; Wang, Yichen

doi:10.1080/21541248.2016.1208792

Cited by 58 publications

(63 citation statements)

References 56 publications

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“…17 DCAMKL1 was originally identified in neurogenesis, but DCAMKL1 has recently been shown to regulate biological processes including cell differentiation, migration, apoptosis, and EMT. 18,19 In clear cell renal carcinoma, Weygant et al 20 found that knockdown of DCAMKL1 could inhibit EMT biomarkers and pluripotency factor expression and markedly suppressed tumor cell migration, invasion, focal adhesion, clonogenic capacity, and drug-resistance. In colorectal cancer, Gao et al 13 reported that DCAMKL1 overexpression significantly accelerated tumor cell migration and invasion, upregulated the mesenchymal markers vimentin and zinc finger E-box -binding homeobox 1 (ZEB1) expression, and downregulated the epithelial marker E-cadherin expression.…”

Section: Discussionmentioning

confidence: 99%

DCAMKL1 is associated with the malignant status and poor outcome in bladder cancer

Zhang¹,

Zhang²,

Guo³

2017

Tumour Biol.

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DCAMKL1 (doublecortin and CaM kinase-like 1) has been found to be overexpressed and function as an oncogene in several types of cancer, but there are limited reports on the role of DCAMKL1 in bladder cancer. The messenger RNA and protein expression of DCAMKL1 in bladder cancer tissues and cell lines was measured by quantitative reverse transcription polymerase chain reaction, western blotting, or immunohistochemistry. The correlation between DCAMKL1 protein expression and clinicopathological characteristics was analyzed. Univariate and multivariate Cox regression models were adopted to evaluate prognostic significance of DCAMKL1 in bladder cancer patients. In our results, DCAMKL1 messenger RNA and protein were overexpressed in bladder cancer tissues compared with adjacent normal tissues. DCAMKL1 protein overexpression was positively associated with clinical stage, muscularis invasion, lymph node metastasis, and distant metastasis. The univariate and multivariate analyses suggested DCAMKL1 protein overexpression was an unfavorable prognostic factor in bladder cancer patients. In conclusion, DCAMKL1 is an independent poor prognostic factor for bladder cancer patients.

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Section: Discussionmentioning

confidence: 99%

DCAMKL1 is associated with the malignant status and poor outcome in bladder cancer

Zhang¹,

Zhang²,

Guo³

2017

Tumour Biol.

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“…DCLK1 is a member of the doublecortin (DCX) superfamily, which also includes DCX, DCDC2, and retinitis pigmentosa 1 (RP1), all of which are implicated in human disease (15,(18)(19)(20)(21)(22). At its N-terminus, DCLK1 contains two tandem DCX domains (DC1 or N-DC: aa 54-152 and DC2 or C-DC: aa 180-263)( Figure S1A), which are highly conserved among other family members (6,18,(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Autoregulatory control of microtubule binding in the oncogene, doublecortin-like kinase 1

Rogers

Ramkumar

Downing

et al. 2020

Preprint

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The microtubule-associated protein (MAP), doublecortin-like kinase 1 (DCLK1), is highly expressed in a range of cancers and is a prominent therapeutic target for the development of kinase inhibitors. However, the physiological roles of its kinase activity and how DCLK1 kinase activity is regulated remain elusive. Here we employ in vitro reconstitution with purified proteins to analyze the role of DCLK1 kinase activity in regulating microtubule binding. We find that DCLK1 autophosphorylates a single residue within its C-terminal tail to restrict its kinase activity and prevent aberrant hyperphosphorylation within its microtubule-binding domain. Removal of the C-terminal tail or mutation of this residue causes an increase in phosphorylation largely within the doublecortin 2 (DC2) domain, which dramatically reduces the microtubule affinity of DCLK1. Therefore, autophosphorylation at specific sites within DCLK1 have diametric effects on the molecule's ability to associate with microtubules. Overall, our results suggest a mechanism by which DCLK1 modulates its own kinase activity to tune its microtubule binding affinity, providing molecular insights into a unique form of autoregulatory control over microtubule binding activity within the broader family of MAPs. These results provide useful molecular insights for future therapeutic efforts related to DCLK1's role in cancer development and progression. Author ContributionsM.R., A.R., and K.M.O.M. conceived of the project and designed the experiments. M.R., A.R., A.D., J.C. and H.B. cloned all DCLK1 constructs and purified the recombinant proteins. M.R. performed the in vitro TIRF-M experiments, the kinase assays, the sucrose gradients, the cleavage assays, and analyzed all of data. A.R. performed the ATPγS kinase assays. D.W.N. created the molecular models. M.R. and K.M.O.M. wrote the manuscript with input from all authors.

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“…Experiments with human colon cancer cells (hCCC) and CRCs have similarly confirmed a critical role of DCLK1 in maintaining spheroidal/tumorous growths of hCCCs, in vitro and in vivo (3, 5, 12, 20, 23–25). A subset of DCLK1+CSCs was reported to overcome inhibitory effects of chemopreventive/chemotherapeutic agents via autophagic survival; loss of DCLK1 combined with chemopreventive agents was required for eliminating CSCs to avoid relapse of the disease (3).…”

Section: Introductionmentioning

confidence: 85%

“…A critical role of DCLK1 was reported in mouse pancreatic/colon carcinogenesis (discussed in ref. 20), and believed to specifically mark CSCs, but not normal stem cells (6). Several reports, however, suggest that DCLK1 probably marks both normal and cancer stem cells (5, 12, 202), including specialized tuft cells (21–23).…”

Section: Introductionmentioning

confidence: 99%

FOXD3 Regulates CSC Marker, DCLK1-S, and Invasive Potential: Prognostic Implications in Colon Cancer

Sarkar

O’Connell

Okugawa

et al. 2017

Molecular Cancer Research

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The 5′ (α)-promoter of the human doublecortin-like kinase 1 (DCLK1) gene becomes epigenetically silenced during colon carcinogenesis, resulting in loss of expression of the canonical long(L)-isoform1 (DCLK1-L) in human colon adenocarcinomas (hCRCs). Instead, hCRCs express a short(S)-isoform2 (DCLK1-S) from an alternate (β)-promoter of DCLK1. The current study, examined if the transcriptional activity of the (β)-promoter is suppressed in normal versus cancerous cells. On the basis of in silico and molecular approaches, it was discovered that FOXD3 potently inhibits the transcriptional activity of the (β)-promoter. FOXD3 becomes methylated in human colon cancer cells (hCCC), with loss of FOXD3 expression, allowing expression of the DCLK1(S) variant in hCCCs/hCRCs. Relative levels of FOXD3/DCLK1(S/L) were measured in a cohort of CRC patient specimens (n = 92), in relation to overall survival (OS). Patients expressing high DCLK1(S), with or without low FOXD3, had significantly worse OS compared with patients expressing low DCLK1(S). The relative levels of DCLK1-L did not correlate with OS. In a pilot retrospective study, colon adenomas from high-risk patients (who developed CRCs in <15 years) demonstrated significantly higher staining for DCLK1(S) + significantly lower staining for FOXD3, compared with adenomas from low-risk patients (who remained free of CRCs). Latter results strongly suggest a prognostic value of measuring DCLK1(S)/FOXD3 in adenomas. Overexpression of DCLK1(S), but not DCLK1(L), caused a significant increase in the invasive potential of hCCCs, which may explain worse outcomes for patients with high DCLK1-S–expressing tumors. On the basis of these data, FOXD3 is a potent repressor of DCLK1-S expression in normal cells; loss of FOXD3 in hCCCs/hCRCs allows upregulation of DCLK1-S, imparting a potent invasive potential to the cells.

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Functional implication of Dclk1 and Dclk1-expressing cells in cancer

Cited by 58 publications

References 56 publications

DCAMKL1 is associated with the malignant status and poor outcome in bladder cancer

DCAMKL1 is associated with the malignant status and poor outcome in bladder cancer

Autoregulatory control of microtubule binding in the oncogene, doublecortin-like kinase 1

FOXD3 Regulates CSC Marker, DCLK1-S, and Invasive Potential: Prognostic Implications in Colon Cancer

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