4.7 Article

The phosphatase CTDSPL2 is phosphorylated in mitosis and a target for restraining tumor growth and motility in pancreatic cancer

Journal

CANCER LETTERS
Volume 526, Issue -, Pages 53-65

Publisher

ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.11.018

Keywords

CTDSPL2; Mitosis; Phosphorylation; CDK1; Pancreatic cancer; p21; p27

Categories

Funding

  1. Fred & Pamela Buffett Cancer Center Support Grant [P30 CA036727]
  2. National Institutes of Health (NIH) [R01 GM109066]

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CTDSPL2, phosphorylated by CDK1 in mitosis, plays a crucial role in regulating cell mitosis, proliferation, and motility in pancreatic cancer. Depletion of CTDSPL2 or using a phosphorylation-deficient mutant hindered tumor growth in xenograft models. Downstream regulators of CTDSPL2, p21 and p27, were identified, providing an alternative molecular target for pancreatic cancer treatment.
Carboxy-terminal domain (CTD) small phosphatase like 2 (CTDSPL2), also known as SCP4 or HSPC129, is a new member of the small CTD phosphatase (SCP) family and its role in cancers remains unclear. Here, we used a Phos-tag technique to screen a series of phosphatases and identified CTDSPL2 as a mitotic regulator. We demonstrated that CTDSPL2 was phosphorylated at T86, 5104, and 5134 by cyclin-dependent kinase 1 (CDK1) in mitosis. Depletion of CTDSPL2 led to mitotic defects and prolonged mitosis. Resultantly, CTDSPL2 deletion restrained proliferation, migration, and invasion in pancreatic cancer cells. We further confirmed the dominant negative effects of a phosphorylation-deficient mutant form of CTDSPL2, implying the biological significance of CTDSPL2 mitotic phosphorylation. Moreover, RT2 cell cycle array analysis revealed p21 and p27 as downstream regulators of CTDSPL2, and inhibition of p21 and/or p27 partially rescued the phenotype in CTDSPL2-deficient cell lines. Importantly, both CTDSPL2 depletion and phosphorylation-deficient mutant CTDSPL2 hindered tumor growth in xenograft models. Together, our findings for the first time highlight the novel role of CTDSPL2 in regulating cell mitosis, proliferation and motility in pancreatic cancer and point out the implications of CTDSPL2 in regulating two critical cell cycle participants (p21 and p27), providing an alternative molecular target for pancreatic cancer treatment.

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