Related Experiment Video

Updated: Sep 6, 2025

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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Published on: March 27, 2020

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

Yongji Zeng1, Ling Yin1, Jiuli Zhou1,2

  • 1Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.

Oncogene
|July 2, 2022
PubMed

Insights

Paclitaxel resistance in pancreatic ductal adenocarcinoma (PDAC) can be overcome by targeting the MARK2-HDAC pathway. Inhibiting MARK2 or HDACs enhances paclitaxel

Area of Science:

  • Molecular Oncology
  • Cancer Therapeutics
  • Cell Biology

Background:

  • Paclitaxel is a widely used chemotherapy agent, but low response rates and drug resistance remain significant challenges in pancreatic ductal adenocarcinoma (PDAC) treatment.
  • Identifying novel targets to enhance paclitaxel efficacy is crucial for improving patient outcomes in PDAC.

Purpose of the Study:

  • To identify key regulators of paclitaxel chemosensitivity in PDAC.
  • To elucidate the molecular mechanisms by which these regulators impact drug response.
  • To explore therapeutic strategies targeting identified pathways to overcome paclitaxel resistance.

Main Methods:

  • Utilized a Phos-tag-based kinome-wide screen to identify critical regulators.
  • Investigated the role of MARK2 in paclitaxel response through phosphorylation studies with CDK1.
  • Examined the MARK2-HDAC-YAP signaling axis and its regulation of gene expression.
  • Validated findings in PDAC organoid and animal models, correlating molecular markers with patient data.

Main Results:

  • MARK2 was identified as a critical regulator of paclitaxel chemosensitivity in PDAC.
  • MARK2 phosphorylation by CDK1 is essential for regulating mitotic progression and paclitaxel cytotoxicity.
  • MARK2 directly phosphorylates HDAC4, promoting YAP activation and paclitaxel-induced gene expression.
  • Combination therapy of HDAC inhibition and paclitaxel overcame chemoresistance in preclinical models.
  • Upregulated MARK2, HDACs, and YAP expression correlates with PDAC patient status.

Conclusions:

  • The MARK2-HDAC axis is a critical pathway regulating paclitaxel response in PDAC.
  • Targeting MARK2 or class IIa HDACs potentiates paclitaxel efficacy by inducing mitotic abnormalities.
  • The MARK2-HDAC axis represents a druggable target for overcoming chemoresistance in PDAC.

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