Zinc finger protein 746 promotes colorectal cancer progression via c-Myc stability mediated by glycogen synthase kinase 3β and F-box and WD repeat domain-containing 7

Ji Hoon Jung; Deok-Beom Jung; Hyunseok Kim; Hyemin Lee; Shi-Eun Kang; Sanjay K Srivastava; Miyong Yun; Sung-Hoon Kim

doi:10.1038/s41388-018-0225-0

Zinc finger protein 746 promotes colorectal cancer progression via c-Myc stability mediated by glycogen synthase kinase 3β and F-box and WD repeat domain-containing 7

Oncogene. 2018 Jul;37(27):3715-3728. doi: 10.1038/s41388-018-0225-0. Epub 2018 Apr 9.

Authors

Ji Hoon Jung¹, Deok-Beom Jung¹, Hyunseok Kim², Hyemin Lee¹, Shi-Eun Kang³, Sanjay K Srivastava⁴, Miyong Yun⁵, Sung-Hoon Kim⁶

Affiliations

¹ Korean Medicine Tumor Ecosystem Regulation Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
² University Hospital Newark, NJ University Hospital 150 Bergen St, Newark, NJ, 07103, USA.
³ Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine Kyung Hee University, Seoul, Republic of Korea.
⁴ Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA.
⁵ Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine Kyung Hee University, Seoul, Republic of Korea. myyun91@khu.ac.kr.
⁶ Korean Medicine Tumor Ecosystem Regulation Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea. sungkim7@khu.ac.kr.

PMID: 29628506
DOI: 10.1038/s41388-018-0225-0

Abstract

To elucidate the underlying oncogenic mechanism of zinc finger protein 746 (ZNF746), current study was conducted in colorectal cancers (CRCs). Herein, ZNF746 was overexpressed in HCT116, SW620, and SW480 cells, which was supported by CRC tissue microarray and TCGA analysis. Also, DNA microarray revealed the differentially expressed gene profile particularly related to cell cycle genes and c-Myc in ZNF746 depleted HCT116 cells. Furthermore, ZNF746 enhanced the stability of c-Myc via their direct binding through nuclear colocalization by immunoprecipitation and immunofluorescence, while ZNF746 and c-Myc exist mainly in nucleoplasm. Conversely, ZNF746 depletion attenuated phosphorylation of c-Myc (S62) and glycogen synthase kinase 3β (GSK3β) (S9) and also activated p-c-Myc (T58), which was reversed by GSK3 inhibitors such as SB-216763 and Enza. Also, c-Myc degradation by ZNF746 depletion was blocked by knockdown of F-box/WD repeat-containing protein 7 (FBW7) ubiquitin ligase or proteosomal inhibitor MG132. Additionally, the growth of ZNF746 depleted HCT116 cancer cells was retarded with decreased expression of ZNF746 and c-Myc. Overall, these findings suggest that ZNF746 promotes CRC progression via c-Myc stability mediated by GSK3 and FBW7.

Publication types

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

MeSH terms

Animals
Cell Line, Tumor
Colorectal Neoplasms / genetics
Colorectal Neoplasms / pathology*
Cysteine Proteinase Inhibitors / pharmacology
Disease Progression
F-Box-WD Repeat-Containing Protein 7 / genetics
F-Box-WD Repeat-Containing Protein 7 / metabolism*
G1 Phase Cell Cycle Checkpoints / genetics
Gene Expression Profiling
Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
Glycogen Synthase Kinase 3 beta / genetics
Glycogen Synthase Kinase 3 beta / metabolism*
HCT116 Cells
HEK293 Cells
HT29 Cells
Humans
Indoles / pharmacology
Leupeptins / pharmacology
Male
Maleimides / pharmacology
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Transplantation
Oligonucleotide Array Sequence Analysis
Phosphorylation / genetics
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
RNA Interference
RNA, Small Interfering / genetics
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Transplantation, Heterologous

Substances

Cysteine Proteinase Inhibitors
F-Box-WD Repeat-Containing Protein 7
FBXW7 protein, human
Indoles
Leupeptins
MYC protein, human
Maleimides
Proto-Oncogene Proteins c-myc
RNA, Small Interfering
Repressor Proteins
SB 216763
ZNF746 protein, human
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
benzyloxycarbonylleucyl-leucyl-leucine aldehyde