MiR-26a-1 Promotes DNA Damage Repair by Inhibiting Sirt1 and KDM5A in Human Liver Cancer Stem Cells

Abstract Background: Although miR-26a-1 was down-regulated expressin in several cancers, the role of miR-26a-1in malignancies has yet to be systematically elucidated. Methods: RT-PCR, Western blotting and tumorigenesis test in vitro and in vivo were performed to analyze the signaling pathway. Results: miR-26a-1 inhibits the NAD(+)-dependent deacetylase Sirt1 expression by targeting the 3' non-coding region of Sirt1 which enhances the acetylation modification of H4 on the 16th lysine of histone and the expression of protein arginine methyltransferase PRMT6. Therefore, miR-26a-1 promotes arginine methylation modification of POLB (R137) and histone. On the other hand, miR-26a-1 inhibits the expression of KDM5A by targeting its 3' non-coding region, which enhances the methylation modification of histone H3 ysine 4. Moreover, miR-26a-1 enhances the expression of histone methyltransferase SETD2 dependent on H3K4me3 and further increases the trimethylation modification of the histone H3 lysine 36 . Significantly, miR-26a-1 promotes the formation of DNA damage repair complex (Rad51-PARP1-ATR-ATM-hMSH6-XRCC-POLB-SKP2) via H3K36me3. In particular, it was found that miR-26a-1 inhibited the function of long non-coding RNA HULC and promoted the formation of DNA damage repair complex. Furthermore, miR-26a-1 promotes the DNA damage repair ability by promoting the DNA damage repair complex to bind to the DNA damage site, thereby inhibiting the DNA damage of liver cancer stem cells. In particular, miR-26a-1 enhanced the binding of H3F3A to Skp2, CUL1, and F-box at the DNA damage site and enhanced the protein ubiquitination modification of H3F3A, which promoted Histone H3 replaces H3F3A by degrading H3F3A, realizing the renewal of histones after DNA damage repair. It was further found that miR-26a-1 inhibited the formation and instability of DNA microsatellites by promoting DNA damage repair, thereby affecting the expression of several cyclins and protein kinases in liver cancer stem cells, such as, inhibiting CDK2 and CyclinE , CDK4, CyclinD1, CDK6, CDK8, CyclinM2, CDK15, pRB, PCNA, MAP3K2, PGK1 and promoting RB, P18, P21/WAF1/Cip1, and thus inhibited the growth of liver cancer stem cells. Strikingly, the rescued-test further confirmed that excessive Sirt1 and KDM5A abrogated the oncogenic function of miR-26a-1. Conclusions: miR26a-1 may acts as the potential biomarker and therapeutic target for liver cancer.

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Mutant MEG3 Enhances the Activity of Telomerase by Increasing DNA Damage Repair in Human Liver Cancer Stem Cells

10.21203/rs.3.rs-486093/v1 ◽

2021 ◽

Author(s):

Shuting Song ◽

Sijie Xie ◽

Rushi Qin ◽

Yanan Lu ◽

Liyan Wang ◽

...

Keyword(s):

Stem Cells ◽

Dna Damage ◽

Cancer Stem Cells ◽

Liver Cancer ◽

Human Liver ◽

Dna Damage Repair ◽

Liver Cancer Stem Cells ◽

Damage Repair ◽

Human Liver Cancer

Abstract Background: Long noncoding RNAs have recently considered as central regulators in diverse biological processes and emerged as vital players controlling tumorigenesis. Although wild MEG3 acts as a suppressor in several cancers, the function of mutant MEG3 is also unclear during tumorigenesis.Methods: Lentivalus infection,RT-PCR,Western blotting and tumorigenesis test in vitro and in vivo were performed.Results: our results suggest that mutant MEG3 promotes the growth of human liver cancer stem cells in vivo and in vitro.Mechanistically, our results show that mutant MEG3 enhances acetylation modification of HistoneH4 on K16.Then, mutant MEG3 enhances the expression of SETD2 dependent on H4K16Ac.Moreover, mutant MEG3 increases the DNA damage repair through SETD2.Ultimately, mutant MEG3 increases the telomeras activity dependent on DNA damage repair.Strikingly,TERT determines the cancerous function of mutant MEG3 in liver cancer stem cells. Therefore, we shed light on the fact that targeting mutant MEG3 could be a viable approach for cancer treatment.Conclusions: these observations will play an important role in finding effective tumor treatment targets.

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Quinacrine and curcumin synergistically increased the breast cancer stem cells death by inhibiting ABCG2 and modulating DNA damage repair pathway

The International Journal of Biochemistry & Cell Biology ◽

10.1016/j.biocel.2019.105682 ◽

2020 ◽

Vol 119 ◽

pp. 105682 ◽

Cited By ~ 3

Author(s):

Deepika Nayak ◽

Neha Tripathi ◽

Deepika Kathuria ◽

Sumit Siddharth ◽

Anmada Nayak ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Dna Damage ◽

Cancer Stem Cells ◽

Dna Damage Repair ◽

Breast Cancer Stem Cells ◽

Repair Pathway ◽

Damage Repair ◽

Cells Death

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BC-02 eradicates liver cancer stem cells by upregulating the ROS-dependent DNA damage

International Journal of Oncology ◽

10.3892/ijo.2017.4159 ◽

2017 ◽

Vol 51 (6) ◽

pp. 1775-1784 ◽

Cited By ~ 9

Author(s):

Chunhui Dou ◽

Chunyan Fang ◽

Yan Zhao ◽

Xiaoyan Fu ◽

Yufei Zhang ◽

...

Keyword(s):

Stem Cells ◽

Dna Damage ◽

Cancer Stem Cells ◽

Liver Cancer ◽

Liver Cancer Stem Cells

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DNA Damage Repair Pathways in Cancer Stem Cells

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-11-1040 ◽

2012 ◽

Vol 11 (8) ◽

pp. 1627-1636 ◽

Cited By ~ 89

Author(s):

Marcello Maugeri-Saccà ◽

Monica Bartucci ◽

Ruggero De Maria

Keyword(s):

Stem Cells ◽

Dna Damage ◽

Cancer Stem Cells ◽

Dna Damage Repair ◽

Damage Repair ◽

Repair Pathways

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Faculty Opinions recommendation of Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1087486.540536 ◽

2007 ◽

Author(s):

Lucio Comai

Keyword(s):

Stem Cells ◽

Dna Damage ◽

Dna Damage Repair ◽

Haematopoietic Stem Cells ◽

Damage Repair

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The inhibition of ABCB1/MDR1 or ABCG2/BCRP enables doxorubicin to eliminate liver cancer stem cells

Scientific Reports ◽

10.1038/s41598-021-89931-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Wang Yin ◽

Dongxi Xiang ◽

Tao Wang ◽

Yumei Zhang ◽

Cuong V. Pham ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Liver Cancer ◽

High Performance ◽

Annexin V ◽

Intracellular Concentration ◽

Liver Cancer Stem Cells ◽

Chemotherapy Agent ◽

Future Strategy ◽

Annexin V Assay

AbstractTwo ATP-binding cassette transporters, ABCB1/MDR1 and ABCG2/BCRP, are considered the most critical determinants for chemoresistance in hepatocellular carcinoma. However, their roles in the chemoresistance in liver cancer stem cells remain elusive. Here we explored the role of inhibition of MDR1 or ABCG2 in sensitizing liver cancer stem cells to doxorubicin, the most frequently used chemotherapeutic agent in treating liver cancer. We show that the inhibition of MDR1 or ABCG2 in Huh7 and PLC/PRF/5 cells using either pharmacological inhibitors or RNAi resulted in the elevated level of intracellular concentration of doxorubicin and the accompanied increased apoptosis as determined by confocal microscopy, high-performance liquid chromatography, flow cytometry, and annexin V assay. Notably, the inhibition of MDR1 or ABCG2 led to the reversal of the chemoresistance, as evident from the enhanced death of the chemoresistant liver cancer stem cells in tumorsphere-forming assays. Thus, the elevation of effective intracellular concentration of doxorubicin via the inhibition of MDR1 or ABCG2 represents a promising future strategy that transforms doxorubicin from a traditional chemotherapy agent into a robust killer of liver cancer stem cells for patients undergoing transarterial chemoembolization.

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