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Review
. 2023 Nov 16;24(22):16407.
doi: 10.3390/ijms242216407.

Epigenetic Landscape and Therapeutic Implication of Gene Isoforms of Doublecortin-Like Kinase 1 for Cancer Stem Cells

Landon L Moore  1 , Courtney W Houchen  1   2   3
Affiliations
Review

Epigenetic Landscape and Therapeutic Implication of Gene Isoforms of Doublecortin-Like Kinase 1 for Cancer Stem Cells

Landon L Moore et al. Int J Mol Sci. .

Abstract

While significant strides have been made in understanding cancer biology, the enhancement in patient survival is limited, underscoring the urgency for innovative strategies. Epigenetic modifications characterized by hereditary shifts in gene expression without changes to the DNA sequence play a critical role in producing alternative gene isoforms. When these processes go awry, they influence cancer onset, growth, spread, and cancer stemness. In this review, we delve into the epigenetic and isoform nuances of the protein kinase, doublecortin-like kinase 1 (DCLK1). Recognized as a hallmark of tumor stemness, DCLK1 plays a pivotal role in tumorigenesis, and DCLK1 isoforms, shaped by alternative promoter usage and splicing, can reveal potential therapeutic touchpoints. Our discussion centers on recent findings pertaining to the specific functions of DCLK1 isoforms and the prevailing understanding of its epigenetic regulation via its two distinct promoters. It is noteworthy that all DCLK1 isoforms retain their kinase domain, suggesting that their unique functionalities arise from non-kinase mechanisms. Consequently, our research has pivoted to drugs that specifically influence the epigenetic generation of these DCLK1 isoforms. We posit that a combined therapeutic approach, harnessing both the epigenetic regulators of specific DCLK1 isoforms and DCLK1-targeted drugs, may prove more effective than therapies that solely target DCLK1.

Keywords: DCLK1; cancer stem cells; drug targeting; epigenetics; gene isoforms.

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Conflict of interest statement

C.W.H. has an ownership interest with COARE Holdings, Inc. All remaining authors declare no competing interest.

Figures

Figure 1
Figure 1
Exposure to environmental insults, such as irradiation or inflammation, alter DNA methylation and gene isoforms to promote cancer. (A) Several genes have been identified as having alternative promoters, Promoteralpha and Promoterbeta, with the upstream promoter located near CpG-islands that are the target of DNA methylation. Expression may be primarily from the upstream promoter, but this does not preclude expression from the downstream promoter, which may reflect the homeostatic balance of the individual isoforms and their roles. (B) Upon various environmental exposures, the DNA methylation of the upstream promoter is hypermethylated at nearby CpG sites resulting in the inhibition (arc with crossbar) of the promoter. This may directly or indirectly result in an increase in expression from the downstream promoter, which may affect tumorigenesis via the imbalance between the isoforms and their relative functions. Created with BioRender.com (accessed on 10 October 2023).
Figure 2
Figure 2
Doublecortin-like kinase-1 (DCLK1) isoforms generated via alternative promoter and alternative RNA splicing. All the four main isoforms contain the kinase domain (green) and its autoregulatory domain (AID) shown in red. Isoforms DCLK1.1 and DCLK1.2 (often referred as DCLK1-L) both contain the microtubule binding domains (DCX, shown in blue) yet differ in their C-terminal domains due to alternative RNA processing (yellow versus orange). From the downstream promoter, two isoforms (sometimes referenced as DCLK1-S) are generated also with distinct C-termini from alternative RNA processing, providing a further means of functional regulation. A short sequence at the N-terminus unique to the two downstream promoter products is shown in grey. Created with BioRender.com (accessed on 10 October 2023).
Figure 3
Figure 3
Proposed model for combined epigenetic drug therapy along with DCLK1 targeted inhibition of cancer stemness to restore homeostasis. Epigenetic inhibitor drugs, preferably with minimal side-effects, are used to oppose the epigenetic marks, inhibiting the expression of tumor suppressors and oncogene-opposing isoforms. Simultaneously, the inhibition of DCLK1, either isoform-specific (CBT-15/511) or in general, by targeting the kinase activity (DCLK1-IN-1) is used to block cancer stem cells that promote chemoresistance. Created with BioRender.com (accessed on 10 October 2023).
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