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LncRNA ZNF674-AS1 regulates granulosa cell glycolysis and proliferation by interacting with ALDOA.

ABSTRACT: Granulosa cell (GC) is a critical somatic component of ovarian follicles to support oocyte development, while the regulatory role of long noncoding RNA (lncRNA) in GCs is largely unknown. Here, we identified a down-regulated lncRNA ZNF674-AS1 in GCs from patients with biochemical premature ovarian insufficiency (bPOI), and its expression correlates with serum levels of clinical ovarian reserve indicators. Functional experiments showed that ZNF674-AS1 is induced by energy stress, and regulates the proliferation and glycolysis of GCs, which possibly leads to follicular dysfunction. Mechanistically, low-expressed ZNF674-AS1 reduced the enzymatic activity of aldolase A (ALDOA), concomitant with promoting the association between ALDOA and v-ATPase to activate the lysosome localized AMP-activated protein kinase (AMPK). These findings identified a new lncRNA-ALDOA complex through which ZNF674-AS1 exerts its functions, expanding the understanding of epigenetic regulation of GCs function and POI pathogenesis.

SUBMITTER: Li D

PROVIDER: S-EPMC8124069 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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LncRNA ZNF674-AS1 regulates granulosa cell glycolysis and proliferation by interacting with ALDOA.

Li Duan D Wang Xiaoyan X Li Guangyu G Dang Yujie Y Zhao Shidou S Qin Yingying Y

Cell death discovery 20210516 1

Granulosa cell (GC) is a critical somatic component of ovarian follicles to support oocyte development, while the regulatory role of long noncoding RNA (lncRNA) in GCs is largely unknown. Here, we identified a down-regulated lncRNA ZNF674-AS1 in GCs from patients with biochemical premature ovarian insufficiency (bPOI), and its expression correlates with serum levels of clinical ovarian reserve indicators. Functional experiments showed that ZNF674-AS1 is induced by energy stress, and regulates th ...[more]

PMID: 33993190

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Project description:BackgroundPremature ovarian insufficiency (POI) is an ovarian dysfunction disorder that significantly impacts female fertility. Ovarian granulosa cells (GCs) are crucial somatic components supporting oocyte development that rely on glycolysis for energy production, which is essential for follicular growth. Hypoxia-induced exosomal circRNAs regulate glycolysis, but their biological functions and molecular mechanisms in POI are largely unexplored. The present comprehensive investigation revealed a substantial reduction in ovarian glycolysis levels in POI rats. Notably, hypoxia-induced exosomes originating from mesenchymal stem cells (HM-Exs) exhibit a remarkable capacity to enhance ovarian glycolysis, mitigate GCs apoptosis, reinstate disrupted estrous cycles, modulate sex hormone levels, and curtail the presence of atretic follicles. These restorative actions collectively contribute to fostering fertility revival in POI-afflicted rats.MethodsCyclophosphamide was administered for 2 weeks to induce POI rat model, and POI rats were randomly divided into three groups and treated with PBS, NM-Exs and HM-Exs, respectively. Ovarian function and fertility were assessed at the end of the study and ovarian tissues were collected for analysis of energy metabolites. The relationship between circDennd2a and POI was explored in vitro by qRT-PCR, Western blotting, CCK-8 assay, EdU staining, TUNEL staining, extracellular acidification rate (ECAR) measurements, and ATP, lactate and pyruvate level assays.ResultsOur findings revealed depletion of circDennd2a in serum samples and GCs from individuals suffering from POI. The introduction of HM-Exs-derived circDennd2a (HM-Exs-circDennd2a) effectively counteracted GCs apoptosis by enhancing glycolytic processes and driving cellular proliferation. CircDennd2a interacted with lactate dehydrogenase A (LDHA), which served as a catalyst to increase LDHA enzymatic activity and facilitate the conversion of NADH to NAD+. This biochemical cascade worked synergistically to sustain glycolytic function within GCs.ConclusionThis study revealed that HM-Exs-circDennd2a promoted LDHA activity and enhanced GCs glycolytic capacity, both of which support its use as a potential clinical diagnostic and therapeutic target for POI.

Project description:Long non-coding (lnc)RNAs have been recognized as important regulators in gastric cancer. lncRNA GAS8-AS1 is considered a tumor suppressor in multiple types of cancer, such as papillary thyroid carcinoma, ovarian cancer and colorectal cancer. However, the specific role of GAS8-AS1 in gastric cancer remains to be fully elucidated. The aim of the present study was to investigate the role of GAS8-AS1 in gastric cancer and its potential underlying mechanisms of action. The expression levels of GAS8-AS1, microRNA (miR)-21-3p, PTEN and pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in gastric cancer and non-cancerous tissues, as well as in gastric cancer cell lines, were detected using reverse transcription-quantitative PCR. Cell proliferation was detected by using a Cell Counting Kit-8 assay. Cell migration and invasion were detected using a Transwell assay. Results of the present study demonstrated that the expression levels of GAS8-AS1 in gastric cancer tissues were significantly decreased, whereas its expression did not differ among cancer tissues at different clinical stages. Low expression levels of GAS8-AS1 predicted poor 5-year survival rates for 70 patients with gastric adenocarcinoma from the Affiliated Hospital of Xuzhou Medical University (Xuzhou, China) during patient follow-up. In addition, the expression levels of miR-21-3p were markedly increased in cancer tissues, and miR-21-3p expression was negatively associated with the expression of GAS8-AS1. The direct interaction between GAS8-AS1 and miR-21-3p was predicted using the starBase database and was confirmed by using an RNA pull-down assay. In gastric cell lines, the overexpression of GAS8-AS1 reduced the expression levels of mature miR-21-3p but did not affect the expression of miR-21-3p precursor, while the overexpression of miR-21-3p did not, in turn, affect the expression of GAS8-AS1. In addition, the overexpression of GAS8-AS1 inhibited cancer cell proliferation, while the overexpression of miR-21-3p promoted cancer cell proliferation and attenuated the effects of GAS8-AS1. Overexpression of miR-21-3p promoted cancer cell migration and invasion, whereas overexpression of GAS8-AS1 did not affect cell migration or invasion. In summary, results of the present study have demonstrated that GAS8-AS1 acts as a tumor suppressor in gastric cancer, and it may inhibit cancer cell proliferation by downregulating miR-21-3p.

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LncRNA ZNF674-AS1 regulates granulosa cell glycolysis and proliferation by interacting with ALDOA.

Publications

LncRNA ZNF674-AS1 regulates granulosa cell glycolysis and proliferation by interacting with ALDOA.

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