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

Yongji Zeng, Ling Yin, Jiuli Zhou, Renya Zeng, Yi Xiao, Adrian R. Black, Tuo Hu, Pankaj K. Singh, Feng Yin, Surinder K. Batra, Fang Yu, Yuanhong Chen, Jixin Dong

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3859-3875
Number of pages17
JournalOncogene
Volume41
Issue number31
DOIs
StatePublished - Jul 29 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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