JNK-mediated Ser27 phosphorylation and stabilization of SIRT1 promote growth and progression of colon cancer through deacetylation-dependent activation of Snail

Yeon Hwa Lee, Su Jung Kim, Xizhu Fang, Na Young Song, Do Hee Kim, Jinyoung Suh, Hye Kyung Na, Kyung Ok Kim, Jeong Heum Baek, Young Joon Surh

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Sirtuin 1 (SIRT1), an NAD+-dependent histone/protein deacetylase, has multifaceted functions in various biological events such as inflammation, aging, and energy metabolism. The role of SIRT1 in carcinogenesis, however, is still under debate. Recent studies have indicated that aberrant overexpression of SIRT1 is correlated with metastasis and poor prognosis in several types of malignancy, including colorectal cancer. In the present study, we found that both SIRT1 and SIRT1 phosphorylated on serine 27 were coordinately upregulated in colon cancer patients’ tissues and human colon cancer cell lines. This prompted us to investigate a role of phospho-SIRT1 in the context of colon cancer progression. A phosphorylation-defective mutant form of SIRT1, in which serine 27 was substituted by alanine (SIRT1-S27A), exhibited lower protein stability compared to that of wild-type SIRT1. Notably, human colon cancer (HCT-116) cells harboring the SIRT1-S27A mutation showed decreased cell proliferation and reduced capability to form xenograft tumor in athymic nude mice, which was accompanied by diminished transcriptional activity of Snail. HCT-116 cells carrying SIRT1-S27A were less capable of deacetylating the Snail protein, with a concomitant decrease in the levels of interleukin (IL)-6 and IL-8 mRNA transcripts. Taken together, these observations suggest that SIRT1 stabilized through phosphorylation on serine 27 exerts oncogenic effects at least partly through deacetylation-dependent activation of Snail and subsequent transcription of IL-6 and IL-8 in human colon cancer cells.

Original languageEnglish
Pages (from-to)1555-1571
Number of pages17
JournalMolecular Oncology
Volume16
Issue number7
DOIs
Publication statusPublished - 2022 Apr

Bibliographical note

Funding Information:
This study was supported by the Basic Science Research Grant (2021R1A2C2014186 to YJS and 2021R1l1A1A01046540 to SJK) and the BK21 FOUR Program (5120200513755) from the National Research Foundation, Republic of Korea.

Publisher Copyright:
© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

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