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Published on: October 27, 2014
SET7 interacts with HDAC6 and suppresses the development of colon cancer through inactivation of HDAC6
Shi-Lan Zhang1, Xiao Du1, Lin-Na Tan1
1Department of Gastroenterology, The Second Xiangya Hospital, Central South University Changsha 410011, Hunan, P.R. China.
Abstract:
SET7 is the first lysine methyltransferase and plays vital roles in tumorigenesis. This study aims to seek clinical value of SET7 in colorectal cancer (CRC) patients, along with its biological impact on cell proliferation and migration. In patients with CRC, the expression of SET7 in cancer tissue was significantly lower than that in adjacent tissue, and down-regulated SET7 was closely correlated with poor prognosis. Loss-of-function and gain-of-function studies indicated that SET7 inhibited cell proliferation and migration by acting on HDAC6 substrate in colon cancer cells. Besides, the co-immunoprecipitation assay showed that SET7 and HDAC6 can interact reciprocally. The interaction effect between SET7 and HDAC6 could significantly reduce cell viability, scratch healing rate, and migrated cells in colon cancer cells. Instead of acting on each endogenous expression, the results demonstrated that the level of acetylated α-tubulin was greatly decreased in HDAC6 overexpression group, while significantly increased in SET7 overexpressed group. However, changes were partly restored in both SET7 and HDAC6-transfected group. On the contrary, the expression of acetylated α-tubulin protein was significantly increased in HDAC6 knockdown group, but higher in both HDAC6 and SET7 silencing group. These results indicated that SET7 played a role in tumor suppression via increasing levels of acetylated-α-tubulin mediated by HDAC6. In addition, the interaction effect significantly decreased the ratios of p-ERK/ERK, which indicated that it may partly suppress ERK signaling pathway. In conclusion, SET7 is a promising therapeutic target for preventing metastasis and improving prognosis in colon cancer.
Insights
SET7, a tumor suppressor, is downregulated in colorectal cancer (CRC) and inhibits cell proliferation and migration. SET7 interacts with HDAC6, increasing acetylated α-tubulin and suppressing tumor growth, offering a potential therapeutic target for colon cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- SET7, the first identified lysine methyltransferase, is implicated in tumorigenesis.
- SET7 expression is often altered in various cancers, suggesting a role in tumor development.
Purpose of the Study:
- To investigate the clinical significance of SET7 in colorectal cancer (CRC).
- To elucidate the biological mechanisms by which SET7 influences CRC cell proliferation and migration.
Main Methods:
- Analysis of SET7 expression in CRC tissues and correlation with patient prognosis.
- In vitro loss-of-function and gain-of-function studies in colon cancer cells.
- Co-immunoprecipitation assays to assess SET7-HDAC6 interaction.
- Western blotting to evaluate levels of acetylated α-tubulin and p-ERK/ERK.
Main Results:
- SET7 expression was significantly lower in CRC tissues compared to adjacent tissues, correlating with poor prognosis.
- SET7 suppressed colon cancer cell proliferation and migration, partly through interaction with HDAC6.
- SET7-HDAC6 interaction increased acetylated α-tubulin levels and decreased p-ERK/ERK ratios, suggesting tumor-suppressive activity.
- SET7's tumor-suppressive role is mediated by increasing acetylated α-tubulin via HDAC6 and potentially inhibiting the ERK signaling pathway.
Conclusions:
- Downregulated SET7 is associated with poor prognosis in colorectal cancer.
- SET7 functions as a tumor suppressor in colon cancer by modulating HDAC6 activity and acetylated α-tubulin levels.
- SET7 represents a potential therapeutic target for improving prognosis and preventing metastasis in colon cancer.
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