AK-1, a specific SIRT2 inhibitor, induces cell cycle arrest by downregulating Snail in HCT116 human colon carcinoma cells

Min Gyeong Cheon; Wootae Kim; Minji Choi; Ja-Eun Kim

doi:10.1016/j.canlet.2014.10.012

AK-1, a specific SIRT2 inhibitor, induces cell cycle arrest by downregulating Snail in HCT116 human colon carcinoma cells

Cancer Lett. 2015 Jan 28;356(2 Pt B):637-45. doi: 10.1016/j.canlet.2014.10.012. Epub 2014 Oct 12.

Authors

Min Gyeong Cheon¹, Wootae Kim¹, Minji Choi¹, Ja-Eun Kim²

Affiliations

¹ Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea; Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 130-701, Republic of Korea.
² Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea; Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 130-701, Republic of Korea. Electronic address: jekim@khu.ac.kr.

PMID: 25312940
DOI: 10.1016/j.canlet.2014.10.012

Abstract

SIRT2, a member of the sirtuin family, is involved in the regulation of a variety of physiological functions. In addition, SIRT2 has been studied in the context of pathological conditions including neurodegenerative diseases, metabolic syndrome, and cancer. The effect of SIRT2 on cancer cell growth depends on cancer tissue type. To investigate the role of SIRT2 in colon cancer, we treated HCT116 human colon cancer cells with the SIRT2-specific inhibitor AK-1, a cell-permeable benzylsulfonamide. AK-1 treatment induced proteasomal degradation of the Snail transcription factor through inactivation of the NF-κB/CSN2 pathway. Reduction in the level of Snail resulted in upregulation of p21, a cyclin-dependent kinase inhibitor, leading to G1 arrest, slow proliferation, and slow wound-healing activity. The regulation of Snail-p21 axis by AK-1 also occurs in HT-29 colon cancer cells. Therefore, inhibition of SIRT2 using AK-1 would be a beneficial intervention in the treatment of colon cancer.

Keywords: AK-1; Cell cycle; G1 arrest; SIRT2; Snail.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Blotting, Western
Cell Cycle Checkpoints / drug effects*
Cell Proliferation / drug effects
Colonic Neoplasms / drug therapy
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology*
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Humans
RNA, Messenger / genetics
RNA, Small Interfering / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Sirtuin 2 / antagonists & inhibitors*
Sirtuin 2 / genetics
Sirtuin 2 / metabolism
Snail Family Transcription Factors
Sulfonamides / pharmacology*
Transcription Factors / antagonists & inhibitors*
Transcription Factors / genetics
Transcription Factors / metabolism
Tumor Cells, Cultured
Wound Healing / drug effects

Substances

Antineoplastic Agents
CDKN1A protein, human
Cyclin-Dependent Kinase Inhibitor p21
RNA, Messenger
RNA, Small Interfering
Snail Family Transcription Factors
Sulfonamides
Transcription Factors
SIRT2 protein, human
Sirtuin 2