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CN114601929B - Application of IIa type HDAC inhibitor TMP269 in ARID1A deficiency type liver cancer - Google Patents

Application of IIa type HDAC inhibitor TMP269 in ARID1A deficiency type liver cancer Download PDF

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CN114601929B
CN114601929B CN202210477184.5A CN202210477184A CN114601929B CN 114601929 B CN114601929 B CN 114601929B CN 202210477184 A CN202210477184 A CN 202210477184A CN 114601929 B CN114601929 B CN 114601929B
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arid1a
liver cancer
tmp269
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hdac7
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CN114601929A (en
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张珊珊
韩兴华
吴刚
施岚
马筱玲
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Anhui Provincial Hospital First Affiliated Hospital Of Ustc
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Abstract

The application of IIa type HDAC inhibitor TMP269 in ARID1A deficiency liver cancer belongs to the biotechnology field, and IIa type HDACs gene expression is obviously increased after ARID1A is knocked down in wild type liver cancer cells; the level of ubiquitination of cells after ARID1A is knocked down is reduced, and the level of ubiquitination after ARID1A is overexpressed is increased; HDAC7 is highly expressed in liver cancer tissues and is associated with poor prognosis of tumors. The invention uses IIa type HDAC inhibitor TMP269 to treat liver cancer cells, and discovers that the cell proliferation capacity is obviously enhanced after ARID1A is knocked down, and the TMP269 treatment can effectively inhibit the cell proliferation. Therefore, ARID1A deficiency in liver cancer can activate the expression of IIa type HDACs such as HDAC7, and IIa type HDAC inhibitor TMP269 can effectively inhibit ARID1A deficiency type liver cancer.

Description

Application of IIa type HDAC inhibitor TMP269 in ARID1A deficiency type liver cancer
Technical Field
The invention belongs to the technical field of biology, and particularly relates to application of IIa type HDAC inhibitor TMP269 in ARID1A deficiency liver cancer.
Background
Hepatocellular carcinoma (abbreviated as liver cancer) is one of the most common malignant tumors of digestive system, the number of new cases in the year is 6 th and the number of death cases is 2 nd, and the number of annual incidence cases and death cases of liver cancer in China are more than 50% of the total number of the world. Currently, the main treatment modes of liver cancer include surgical excision, chemotherapy and liver transplantation. However, due to the lack of an effective early diagnosis method, most patients have advanced tumors and lost the best opportunity for surgery, and systemic treatment is particularly important, while targeted therapy is an important component of systemic treatment. The targeted drugs approved by the FDA for the treatment of advanced liver cancer at present mainly comprise tyrosine kinase inhibitors (sorafenib, lenvatinib, cabozantine and regorafenib), anti-angiogenesis drugs (ramucirumab) and the like. However, the existing liver cancer targeted drugs still have lower lasting response rate and heavier adverse reactions in clinical treatment, and can not effectively improve survival of patients. Therefore, the molecular mechanism of occurrence and development of liver cancer is further researched, and the exploration of new molecular targeted drugs has important research value.
ARID1A (AT-Rich Interaction Domain 1A) is a subunit with high conservation in a chromatin remodelling complex, has the functions of promoting DNA damage repair, inhibiting cell cycle, accelerating apoptosis, maintaining cell stem property and the like, and is an important cancer inhibiting molecule. Of all known epigenetic regulatory molecules, the ARID1A gene has the highest frequency of mutation in tumors. The oncogenic mutations of ARID1A are distributed over the whole gene length, mainly nonsense mutations and frameshift mutations, which result in loss of ARID1A protein expression and are closely related to tumor progression and poor prognosis. In liver cancer, the ARID1A gene was mutated in 10% -15% of cases, next to CTNNB1 and TP53 mutations.
As a cancer suppressor, the development of tumorigenesis caused by the deletion of ARID1A is a difficult problem in clinical treatment, and no method has been available to directly restore its activity in cells, but the downstream key molecules and signaling pathways activated by the ARID1A deletion can be used as targets for tumor treatment. Current studies on ARID 1A-deleted tumors have demonstrated several targets that can be used for therapy: deletion of ARID1A in ovarian clear cell carcinoma resulted in increased methyltransferase EZH2 activity, which resulted in tumors exhibiting superior efficacy against EZH2 inhibitors. In addition, ARID 1A-deficient ovarian clear cell carcinoma also exhibits a strong sensitivity to the YES1 inhibitor Dasatinib (Dasatinib), the mechanism of which is associated with G1-S phase cell cycle arrest. However, the current research on the targeted therapy of ARID 1A-deficient tumors is in basic experiments and early clinical trial states, and is not formally approved for clinical use.
Disclosure of Invention
The invention aims to provide an application of IIa type HDAC inhibitor TMP269 in ARID1A deficiency type liver cancer, so as to overcome the defects of the existing liver cancer therapeutic drugs.
Histone deacetylases (Histone Deacetylases, HDACs) are important epigenetic regulatory factors, which can be classified into 4 classes according to sequence homology, are highly expressed in many tumors, and exert a carcinomatous effect. It can deacetylate histone or non-histone and promote the generation and development of tumor by affecting multiple ways of cell proliferation, apoptosis, DNA damage repair, metastasis, angiogenesis, autophagy, etc. HDAC inhibitors are promising anticancer drugs for the treatment of various tumors such as T cell lymphoma, multiple myeloma, lung cancer, bladder cancer, etc., because they allow the intracellular acetylation homeostasis to be restored. Also, it has been reported that SAHA, an HDAC pan inhibitor, is effective against ARID1A mutant ovarian clear cell carcinoma.
The applicant team of the present invention found that IIa type HDACs (7, 5, 9) gene expression was significantly increased after knocking down ARID1A in wild type hepatoma cells in RNA-seq. Then, the liver cancer cell line is subjected to the ubiquitination detection, and the detection shows that the ubiquitination level of the cells after the ARID1A is knocked down is reduced, and the ubiquitination level after the ARID1A is overexpressed is increased. A series of HDACs expression was verified by qRT-PCR experiments, and HDAC7 elevation was found to be most pronounced. After analysis of the TCGA database, HDAC7 was found to be highly expressed in liver cancer tissues and correlated with poor prognosis of tumors. Plate cloning, CCK8 and EdU experiments prove that the proliferation capacity of liver cancer cells is enhanced after the HDAC7 is excessively expressed, and the proliferation capacity of liver cancer cells is weakened after the HDAC7 is knocked down.
Therefore, the invention provides application of IIa type HDAC inhibitor TMP269 in preparing a medicament for treating ARID1A deficiency type liver cancer. The invention uses IIa type HDAC inhibitor TMP269 to treat liver cancer cells, and discovers that the cell proliferation capacity is obviously enhanced after ARID1A is knocked down, and the TMP269 treatment can effectively inhibit the cell proliferation. Therefore, ARID1A deficiency in liver cancer can activate the expression of IIa type HDACs such as HDAC7, and IIa type HDAC inhibitor TMP269 can effectively inhibit ARID1A deficiency type liver cancer.
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The present invention will be described in further detail with reference to the following examples and drawings.
FIG. 1 shows that knocking down ARID1A up-regulates IIa type HDACs gene expression in hepatoma cells.
FIG. 2 shows that ARID1A loss in liver cancer cells inhibits cell acetylation.
FIG. 3 shows that ARID1A deficiency in hepatoma cells resulted in increased expression of HDAC7.
Fig. 4 shows that HDAC7 is highly expressed in liver cancer tissue and is associated with poor prognosis of tumors.
Fig. 5 shows overexpression of HDAC7 in hepatoma cell Huh 7.
Fig. 6 shows that knock down HDAC7 inhibits malignant proliferation of hepatoma cells.
FIG. 7 shows that TMP269 inhibits proliferation of ARID 1A-deficient liver cancer cells.
Detailed Description
Example one, ARID1A deletion upregulates IIa class HDACs Gene expression in hepatoma cells
1. A cell strain for stably knocking down ARID1A is constructed in ARID1A wild liver cancer cell Huh 7. The experimental method comprises the following steps: HEK293T cells were co-transfected with shControl/shARID1A plasmid and packaging plasmid, and virus supernatant was collected after 48 h. Wild liver cancer cells Huh7 were transfected with virus solution, and after 48h, huh7 cells stably expressing shControl and shARID1A were established by screening with 2. Mu.g/ml puromycin.
2. RNA-seq was performed using shControl and shARID1A Huh7 cells, and GO enrichment analysis was performed on differentially expressed genes. Up-regulated genes following the knockdown of ARID1A were found to be enriched in multiple pathways associated with chromatin organization, DNA transcription, ribosomal generation, with chromatin modification pathways leading (see fig. 1A).
3. The heat-map results show the gene expression profile (fold change in expression from high to low following ARID1A knockdown) associated with deacetylase activity for two groups of cells in the RNA-seq data. The results showed that class II HDACs ( HDACs 7, 5, 9, 10) gene expression was significantly increased after the arod 1A knockdown (see fig. 1B).
Example two ARID1A deficiency in liver cancer cells inhibits cell acetylation
1. The knockdown/overexpression of ARID1A was transfected in wild-type hepatoma cell Huh 7. (1) Gene knockout experiment method: the target gene siRNA plasmid was transfected into cells using lipo3000, and after 48 hours, RNA and protein were extracted to detect the expression level. (2) Gene overexpression Experimental method: the expression level was detected by transfecting the plasmid overexpressing ARID1A into cells using lipo3000, extracting RNA and protein after 48 h.
2. Western Blotting was used to detect the level of cellular ubiacetylation. The experimental method comprises the following steps: (1) And collecting the cells to be tested by using the cell lysate, and extracting the total protein of the cells. (2) An 8% SDS polyacrylamide gel was prepared and subjected to SDS-PAGE electrophoresis. (3) after electrophoresis, the membrane was turned on at 250mA for 2.5 hours. After electrophoresis, PVDF membrane is put into sealing liquid and sealed for 2 hours at room temperature. (4) The primary antibody was diluted with 1 XTBST, membrane was cut to the size of the protein molecular weight and added to the corresponding primary antibody dilution, followed by shaking incubation overnight at 4 ℃. (5) rinsing 3 times with TBST, adding secondary antibody and incubating for 2h at room temperature. (6) TBST was rinsed 3 times, ECL luminescence reagent was added, and the corresponding protein expression was detected using a chemiluminescent instrument. As a result, it was found that the level of ubiacetyl was decreased after knocking down ARID1A, and the level of ubiacetyl was increased after overexpressing ARID1A. (see FIG. 2)
Example III, ARID1A deficiency in liver cancer cells leads to elevated HDAC7 expression
1. The knockdown/overexpression of ARID1A was transfected in wild-type hepatoma cell Huh 7. The experimental method is the same as in example two.
2. A series of HDACs gene expression was verified in Huh7 cells of siNC and siARID1A using qRT-PCR experiments. The experimental method comprises the following steps: primers for the relevant genes were designed based on the published gene sequences of NCBI (https:// www.ncbi.nlm.nih.gov /). The test cells were collected, washed 3 times with pre-chilled PBS, and total RNA of the cells was extracted by Trizol method and reverse transcribed into cDNA. The detection was performed using a fluorescent quantitative PCR apparatus using GAPDH as an internal reference according to the kit instructions. The results showed that HDAC7 elevation was most pronounced (5-fold more than other HDACs) following the knockdown of ARID1A (see figure 3A),
3. ARID1A was knocked down/overexpressed in Huh7 cells and HDAC7 protein levels were detected using Western Blotting. The experimental method is the same as in example two. The results demonstrate that HDAC7 expression is increased after the armd 1A knockdown and HDAC7 expression is decreased after the armd 1A is overexpressed (see fig. 3B).
Example IV, high expression of HDAC7 in liver cancer tissue and associated with poor prognosis of tumors
1. Analysis of the TCGA liver cancer database (https:// portal. Gdc. Cancer. Gov /) results revealed high expression of HDAC7mRNA in liver cancer tissue compared to paracancerous tissue (see FIG. 4A).
2. The total survival curve was generated based on the difference in HDAC7 gene expression, and it was found that the total survival time of liver cancer patients highly expressing HDAC7 was shorter (see fig. 4B).
Example five, high expression of HDAC7 promotes malignant proliferation of liver cancer cells
1. A cell line which stably and excessively expresses HDAC7 is constructed in a liver cancer cell Huh7, and the experimental method is the same as that in the embodiment.
2. The proliferation potency of Empty and HDAC7 OE Huh7 cells was tested using a plate cloning experiment. The experimental method comprises the following steps: (1) Cells were seeded with 500-1000 cells per well using 6-well plates at 37℃with 5% CO 2 The culture was carried out under the condition for 2 weeks, during which time the cell culture medium was changed every 3 days. (2) When cells formed visible clones on the plates, the medium was discarded and fixed with 4% paraformaldehyde for 30min. (3) The fixative was discarded and 1ml of 0.1% crystal violet dye was added to each well for 30min. (4) The dye liquor is discarded, and the dye liquor is naturally dried after being lightly washed by tap water, and photographed by an inverted microscope. The results showed that over-expression of HDAC7 significantly promoted proliferation of hepatoma cells (see fig. 5A).
3. The Empty and HDAC7 OE Huh7 cell proliferation capacity was tested using CCK8 experiments. The experimental method comprises the following steps: cells were seeded at 500-1000 cells per well using 96-well plates. CCK8 reagent was added to the cell culture medium at 1:10 at the same time per day at 37℃with 5% CO 2 After 2 hours of cultivation under the condition, the absorbance at 450nm is measured, and the growth curve is drawn by continuously measuring for 4-5 days. The results showed that over-expression of HDAC7 significantly promoted proliferation of hepatoma cells (see fig. 5B).
4. The Empty and HDAC7 OE Huh7 cell proliferation capacity was tested using the EdU assay. The experimental method comprises the following steps: (1) Cells were seeded in 35mm dishes with slides at the bottom. After the cells had grown on the wall, half of the medium was replaced with medium containing 20. Mu.M EdU and the culture was continued for 4h. (2) The medium was discarded and fixed with 4% paraformaldehyde for 15min. (3) The PBT (PBS containing 0.5% Triton X-100) was permeabilized with 3% BSA (PBS) 2 times. (4) The BSA was rinsed 2 times and the EdU reaction was added and incubated for 30min in the dark. (5) rinsing 2 times with BSA, and dying the nuclei for 10min in the dark using Hoechst. (6) After rinsing 2 times with BSA, the liquid was discarded and blocked, and photographed using a laser confocal microscope. The results showed that over-expression of HDAC7 significantly promoted proliferation of hepatoma cells (see fig. 5C).
Example six, knock-down of HDAC7 to inhibit malignant proliferation of hepatoma cells
1. A cell line for stably knocking down HDAC7 is constructed in a liver cancer cell Bel7402, and the experimental method is the same as that in the first embodiment.
2. shControl and shHDAC7 Huh7 cell proliferation potency were examined using plate cloning experiments. The experimental procedure is the same as in example five. The results showed that knockdown HDAC7 significantly inhibited liver cancer cell proliferation (see fig. 6A).
3. shControl and shHDAC7 Huh7 cell proliferation potency were examined using CCK8 experiments. The experimental procedure is the same as in example five. The results showed that knockdown HDAC7 significantly inhibited liver cancer cell proliferation (see fig. 6B).
4. shControl and shHDAC7 Huh7 cell proliferation potency were tested using the EdU assay. The experimental procedure is the same as in example five.
The results showed that knockdown HDAC7 significantly inhibited liver cancer cell proliferation (see fig. 6C).
Example seven, TMP269 inhibits proliferation of ARID 1A-deficient liver cancer cells
1. And constructing a cell strain for stably knocking down ARID1A in a liver cancer cell Huh 7. The experimental procedure was as in example one.
2. Adding 2 μM TMP269 (class IIa HDAC inhibitor) or DMSO to shControl and shARID1A Huh7 cells at 37deg.C, 5% CO 2 Subsequent experiments were performed after 24h of incubation under conditions.
3. The effects of shControl and shrid 1A Huh7 cell proliferation potency and TMP269 treatment on cell proliferation were examined using plate cloning experiments. The experimental procedure is the same as in example five. The results showed that the cell proliferation capacity was significantly enhanced after the ARID1A knockdown, while TMP269 treatment was effective in inhibiting cell proliferation (see FIG. 7A).
4. The effect of shControl and shrid 1A Huh7 cell proliferation potency and TMP269 treatment on cell proliferation was examined using CCK8 experiments. The experimental procedure is the same as in example five. The results showed that the cell proliferation capacity was significantly enhanced after the ARID1A knockdown, while TMP269 treatment was effective in inhibiting cell proliferation (see FIG. 7B).
5. The effect of shControl and shrid 1A Huh7 cell proliferation potency and TMP269 treatment on cell proliferation was examined using the EdU experiment. The experimental procedure is the same as in example five. The results showed that the cell proliferation capacity was significantly enhanced after the ARID1A knockdown, while TMP269 treatment was effective in inhibiting cell proliferation (see FIG. 7C).
The foregoing is merely illustrative and explanatory of the principles of the invention, as various modifications and additions may be made to the specific embodiments described, or similar thereto, by those skilled in the art, without departing from the principles of the invention or beyond the scope of the appended claims.

Claims (2)

  1. The use of class iia HDAC inhibitor TMP269 as the sole active ingredient in the manufacture of a medicament for the treatment of ARID 1A-deficient liver cancer.
  2. 2. The use according to claim 1, wherein the ARID1A deficient liver cancer is capable of activating the expression of class IIa HDACs and the class IIa HDAC inhibitor TMP269 is effective in inhibiting proliferation of ARID1A deficient liver cancer cells.
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CN115998883B (en) * 2023-03-21 2023-09-12 中国医学科学院基础医学研究所 Use of CFLAR inhibitors for the treatment of ARID1A deficient tumors
CN118655319A (en) * 2024-08-21 2024-09-17 浙江省肿瘤医院 Biliary tract cancer immunotherapy prognosis biomarker

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