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ASPP2 inhibits tumor growth by repressing the mevalonate pathway in hepatocellular carcinoma.

ABSTRACT: Cancer is, fundamentally, a disorder of cell growth and proliferation, which requires adequate supplies of energy and nutrients. In this study, we report that the haplo-insufficient tumor suppressor ASPP2, a p53 activator, negatively regulates the mevalonate pathway to mediate its inhibitory effect on tumor growth in hepatocellular carcinoma (HCC). Gene expression profile analysis revealed that the expression of key enzymes in the mevalonate pathway were increased when ASPP2 was downregulated. HCC cells gained higher cholesterol levels and enhanced tumor-initiating capability in response to the depletion of ASPP2. Simvastatin, a mevalonate pathway inhibitor, efficiently abrogated ASPP2 depletion-induced anchorage-independent cell proliferation, resistance to chemotherapy drugs in vitro, and tumor growth in xenografted nude mice. Mechanistically, ASPP2 interacts with SREBP-2 in the nucleus and restricts the transcriptional activity of SREBP-2 on its target genes, which include key enzymes involved in the mevalonate pathway. Moreover, clinical data revealed better prognosis in patients with high levels of ASPP2 and low levels of the mevalonate pathway enzyme HMGCR. Our findings provide functional and mechanistic insights into the critical role of ASPP2 in the regulation of the mevalonate pathway and the importance of this pathway in tumor initiation and tumor growth, which may provide a new therapeutic opportunity for HCC.

SUBMITTER: Liang B

PROVIDER: S-EPMC6828733 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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ASPP2 inhibits tumor growth by repressing the mevalonate pathway in hepatocellular carcinoma.

Liang Beibei B Chen Rui R Song Shaohua S Wang Hao H Sun Guowei G Yang Hao H Jing Wei W Zhou Xuyu X Fu Zhiren Z Huang Gang G Zhao Jian J

Cell death & disease 20191104 11

Cancer is, fundamentally, a disorder of cell growth and proliferation, which requires adequate supplies of energy and nutrients. In this study, we report that the haplo-insufficient tumor suppressor ASPP2, a p53 activator, negatively regulates the mevalonate pathway to mediate its inhibitory effect on tumor growth in hepatocellular carcinoma (HCC). Gene expression profile analysis revealed that the expression of key enzymes in the mevalonate pathway were increased when ASPP2 was downregulated. H ...[more]

PMID: 31685796

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Project description:Background: Bromodomain-containing protein 7 (BRD7) is identified as a transcriptional regulator and plays an important role in the development and progression of various tumors. Our previous study demonstrated that BRD7 acts as a potential tumor suppressor in hepatocellular carcinoma (HCC). However, the specific molecular mechanism underlying the BRD7-mediated inhibition of HCC progression remains poorly understood. Methods: We performed ChIP-seq analysis to investigate the gene network mediated by BRD7. Immunohistochemical analysis was performed to analyze potential associations between the p53 and BRD7 expression and the effect of their overexpression on disease pathogenesis and outcome. In addition, we performed biological function experiments to determine the effect of BRD7 and p53 on these functions that are central to tumorigenesis. Finally, we employed a BALB/c model for execution of xenograft transplants to examine the effect of either overexpressing or under-expressing BRD7 and p53 on tumor growth in mice injected with cells. Results: Our results suggested that BRD7 regulates the p53 pathway. Specifically, BRD7 was demonstrated to upregulate the transcription level of p53 by directly binding to the upstream regulatory region of the p53 transcriptional initiation site, thereby enhancing its promoter activity. Moreover, immunohistochemical analysis showed that wild-type p53 (WTp53) expression is positively associated with BRD7 expression and survival of patients with HCC. Additionally,changes of p53 expression could affect the tumor suppressive role of BRD7 on HCC cell proliferation, migration/invasion, cell-cycle, and tumor growth in vitro and in vivo. Furthermore, changes of BRD7 expression in HCC cells significantly altered the expression of p53 signal-related molecules such as p21, Bax, Bcl2, and cyclin D1, indicating that BRD7 may positively regulate activation of the p53 pathway. Conclusions: Collectively, our results indicated that BRD7 exerts anti-tumor effects in HCC through transcriptionally activating p53 pathway. These critical roles of BRD7may provide some promising diagnostic and therapeutic targets for HCC.

Dataset Information

ASPP2 inhibits tumor growth by repressing the mevalonate pathway in hepatocellular carcinoma.

Publications

ASPP2 inhibits tumor growth by repressing the mevalonate pathway in hepatocellular carcinoma.

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