1. Academic Validation
  2. Cross-talk between CDK4/6 and SMYD2 regulates gene transcription, tubulin methylation, and ciliogenesis

Cross-talk between CDK4/6 and SMYD2 regulates gene transcription, tubulin methylation, and ciliogenesis

  • Sci Adv. 2020 Oct 30;6(44):eabb3154. doi: 10.1126/sciadv.abb3154.
Linda Xiaoyan Li 1 2 Julie Xia Zhou 1 2 Xiaodong Wang 3 Hongbing Zhang 1 2 Peter C Harris 1 2 James P Calvet 3 Xiaogang Li 4 2
Affiliations

Affiliations

  • 1 Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
  • 2 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
  • 3 Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
  • 4 Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA. li.xiaogang@mayo.edu.
Abstract

Dysregulation of cyclin-dependent kinases 4 and 6 (CDK4/6) by unknown mechanisms is highly prevalent in human disease. In this study, we identify direct cross-talk between CDK4/6 and the epigenome via its previously unidentified substrate, SMYD2, a histone/lysine methyltransferase. CDK4/6 positively regulates the phosphorylation and enzymatic activity of SMYD2, while SMYD2 also positively regulates the expression of CDK4/6. We also identify SMYD2 as an α-tubulin methyltransferase, thus connecting CDK4/6-SMYD2 signaling to microtubule dynamics. In addition, depletion or inhibition of CDK4/6 and SMYD2 resulted in increased cilia assembly by affecting (i) microtubule stability and (ii) the expression of IFT20, further connecting CDK4/6-SMYD2 to ciliogenesis. In clinical settings such as breast Cancer and autosomal dominant polycystic kidney disease (ADPKD), targeting the up-regulated CDK4/6 and SMYD2 with inhibitors results in restoration of the primary cilium in tumor and cystic cells, which may normalize cilia-mediated extracellular signals that regulate growth, development, and cellular homeostasis.

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