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MARK2 regulates chemotherapeutic responses through class IIa HDAC-YAP axis in pancreatic cancer

Abstract

Despite paclitaxel’s wide use in cancer treatment, patient response rate is still low and drug resistance is a major clinical obstacle. Through a Phos-tag-based kinome-wide screen, we identified MARK2 as a critical regulator for paclitaxel chemosensitivity in PDAC. We show that MARK2 is phosphorylated by CDK1 in response to antitubulin chemotherapeutics and in unperturbed mitosis. Phosphorylation is essential for MARK2 in regulating mitotic progression and paclitaxel cytotoxicity in PDAC cells. Mechanistically, our findings also suggest that MARK2 controls paclitaxel chemosensitivity by regulating class IIa HDACs. MARK2 directly phosphorylates HDAC4 specifically during antitubulin treatment. Phosphorylated HDAC4 promotes YAP activation and controls expression of YAP target genes induced by paclitaxel. Importantly, combination of HDAC inhibition and paclitaxel overcomes chemoresistance in organoid culture and preclinical PDAC animal models. The expression levels of MARK2, HDACs, and YAP are upregulated and positively correlated in PDAC patients. Inhibition of MARK2 or class IIa HDACs potentiates paclitaxel cytotoxicity by inducing mitotic abnormalities in PDAC cells. Together, our findings identify the MARK2-HDAC axis as a druggable target for overcoming chemoresistance in PDAC.

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Fig. 1: A Phos-tag-based kinome-wide screen identifies MARK2 as a phospho-kinase by CDK1 during antitubulin agent-induced mitotic arrest.
Fig. 2: Phosphorylation of MARK2 is essential for precise mitosis.
Fig. 3: MARK2 inhibition promotes chemosensitivity in human and mouse PDAC cells.
Fig. 4: MARK2 promotes YAP activity by phosphorylating class IIa HDACs.
Fig. 5: HDAC4/7 control chemosensitivity in human and mouse PDAC cells.
Fig. 6: Inhibition of HDAC promotes chemosensitivity in vivo.
Fig. 7: MARK2-HDAC inhibition synergizes with Taxol treatment to induce mitotic defects in PDAC cells.

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Acknowledgements

We thank Dr. Xiao-long Yang (Queens University) for the TetO-shCDK1 HeLa cell line. All fluorescence images were acquired by a Zeiss LSM 800 microscope and processed with accompanying software at the Advanced Microscopy Core at the University of Nebraska Medical Center. Research in the Dong laboratory is supported by Fred & Pamela Buffett Cancer Center Support Grant (P30 CA036727) and R01 GM109066 from the the National Institutes of Health (NIH). We are very grateful to Dr. Joyce Solheim for critical reading and comments on the paper.

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JD and YZ designed the study and wrote the paper. YZ, LY, JZ, RZ, YX, TH, and YC performed the experiments, analyzed the data, and interpreted the results. YC also provided technical support. Feng Y, PKS, and ARB contributed to data analysis and results interpretation. Fang Y performed statistical analysis. SKB provided the mouse PDAC cell lines. All authors approved the paper prior to submission.

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Correspondence to Jixin Dong.

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Zeng, Y., Yin, L., Zhou, J. et al. MARK2 regulates chemotherapeutic responses through class IIa HDAC-YAP axis in pancreatic cancer. Oncogene 41, 3859–3875 (2022). https://doi.org/10.1038/s41388-022-02399-3

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