Association of doublecortin-like kinase 1 with tumor aggressiveness and poor biochemical recurrence-free survival in prostate cancer

Jiang, Donggen; Xiao, Chutian; Xian, Tuzeng; Wang, Lian-Tao; Mao, Yunfei; Zhang, Junfu; Pang, Jun

doi:10.2147/ott.s157295

Cited by 12 publications

(10 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are over 100 discrete forms of cancer, each with multiple causes (52). Numerous studies have found that DCLK1 is upregulated and acts as an oncogene in a range of cancers including pancreatic, colorectal, gastric, bladder, and breast cancer (7)(8)(9)(10)(11)(12)(13)(14). Due to the emerging body of evidence implicating DCLK1 in tumorigenesis, the protein appears to be a promising target for not just one, but for several types of cancers (15)(16)(17).…”

Section: Discussionmentioning

confidence: 99%

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

Rogers

Ramkumar

Downing

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Rogers

Ramkumar

Downing

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The macromolecular machine responsible for accurately segregating chromosomes during eukaryotic cell division is the bipolar mitotic spindle, a structure composed of dynamic microtubules organized by a multitude of MAPs (3,4). DCLK1, formerly known as DCAMKL1 and KIAA0369, is one such MAP that is also upregulated in a range of cancers, such as pancreatic, breast, bladder, colorectal, gastric, and hepatocellular carcinoma (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). As a consequence, many studies have focused on developing small molecule inhibitors against DCLK1 kinase activity in an effort to control cancer growth (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Autoregulatory control of microtubule binding in doublecortin-like kinase 1

Agulto

Rogers

Tan

et al. 2021

eLife

View full text Add to dashboard Cite

The microtubule-associated protein, doublecortin-like kinase 1 (DCLK1), is highly expressed in a range of cancers and is a prominent therapeutic target for kinase inhibitors. The physiological roles of DCLK1 kinase activity and how it is regulated remain elusive. Here, we analyze the role of mammalian DCLK1 kinase activity in regulating microtubule binding. We find that DCLK1 autophosphorylates a 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 within the doublecortin domains, which abolishes microtubule binding. Therefore, autophosphorylation at specific sites within DCLK1 have diametric effects on the molecule's association with microtubules. Our results suggest a mechanism by which DCLK1 modulates its kinase activity to tune its microtubule-binding affinity. These results provide molecular insights for future therapeutic efforts related to DCLK1's role in cancer development and progression.

show abstract

“…These results suggest involvement of the processes regulated by KLF6 in response to BTZ treatment and bridging of those process may result in a treatment resistant phenotype. Apart from this top hit, a number of genes shown to be involved in proliferation of cancer cells were statistically significantly associated with BTZ induced methylation changes, including: ARHGAP26 38 , TBX2 39 , 40 , MAML3 41 , DCLK1 42 , 43 . The “GO cellular components” (Fig.…”

Section: Discussionmentioning

confidence: 99%

Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound

Łuczkowska

Sokołowska

Taryma-Leśniak

et al. 2021

Sci Rep

View full text Add to dashboard Cite

The anticancer activity of bortezomib (BTZ) has been increasingly studied in a number of indications and promising results for the use of this treatment have been shown in neuroblastoma. As BTZ treatment is usually administered in cycles, the development of resistance and side effects in patients undergoing therapy with BTZ remains a major challenge for the clinical usage of this compound. Common resistance development also means that certain cells are able to survive BTZ treatment and bypass molecular mechanisms that render BTZ anticancer activity. We studied the methylome of neuroblastoma cells that survived BTZ treatment. Our results indicate that BTZ induces pronounced genome wide methylation changes in cells which recovered from the treatment. Functional analyses of identified methylation changes demonstrated they were involved in key cancer pathology pathways. These changes may allow the cells to bypass the primary anticancer activity of BTZ and develop a treatment resistant and proliferative phenotype. To study whether cells surviving BTZ treatment acquire a proliferative phenotype, we repeatedly treated cells which recovered from the first round of BTZ treatment. The repetitive treatment led to induction of the extraordinary proliferative potential of the cells, that increased with subsequent treatments. As we did not observe similar effects in cells that survived treatment with lenalidomide, and non-treated cells cultured under the same experimental conditions, this phenomenon seems to be BTZ specific. Overall, our results indicate that methylation changes may play major role in the development of BTZ resistance.

show abstract

Association of doublecortin-like kinase 1 with tumor aggressiveness and poor biochemical recurrence-free survival in prostate cancer

Cited by 12 publications

References 27 publications

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

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

Autoregulatory control of microtubule binding in doublecortin-like kinase 1

Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound

Contact Info

Product

Resources

About