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PKM2-TMEM33 axis regulates lipid homeostasis in cancer cells by controlling SCAP stability

ABSTRACT: The pyruvate kinase M2 isoform (PKM2) is preferentially expressed in cancer cells to regulate anabolic metabolism. Although PKM2 was recently reported to regulate lipid homeostasis, the molecular mechanism remains unclear. Herein we discovered an ER transmembrane protein 33 (TMEM33) as a downstream effector of PKM2 that regulates activation of SREBPs and lipid metabolism. Loss of PKM2 leads to up-regulation of TMEM33, which recruits RNF5, an E3 ligase, to promote SREBP-cleavage activating protein (SCAP) degradation. TMEM33 is transcriptionally regulated by nuclear factor erythroid 2-like 1 (NRF1), whose cleavage and activation are controlled by PKM2 levels. Total plasma cholesterol levels are elevated by either treatment with PKM2 tetramer promoting agent TEPP-46, or by global PKM2 knockout in mice, highlighting the essential function of PKM2 in lipid metabolism. Although depletion of PKM2 decreases cancer cell growth, global PKM2 knockout accelerates allografted tumor growth. Together, our findings reveal the cell autonomous and systemic effects of PKM2 in lipid homeostasis and carcinogenesis, as well as TMEM33 as a bona fide regulator of lipid metabolism.

SUBMITTER: Dr. Fabao Liu

PROVIDER: S-SCDT-EMBOJ-2021-108065 | biostudies-other |

REPOSITORIES: biostudies-other

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PKM2-TMEM33 axis regulates lipid homeostasis in cancer cells by controlling SCAP stability.

Project description:The pyruvate kinase M2 isoform (PKM2) is preferentially expressed in cancer cells to regulate anabolic metabolism. Although PKM2 was recently reported to regulate lipid homeostasis, the molecular mechanism remains unclear. Herein, we discovered an ER transmembrane protein 33 (TMEM33) as a downstream effector of PKM2 that regulates activation of SREBPs and lipid metabolism. Loss of PKM2 leads to up-regulation of TMEM33, which recruits RNF5, an E3 ligase, to promote SREBP-cleavage activating protein (SCAP) degradation. TMEM33 is transcriptionally regulated by nuclear factor erythroid 2-like 1 (NRF1), whose cleavage and activation are controlled by PKM2 levels. Total plasma cholesterol levels are elevated by either treatment with PKM2 tetramer-promoting agent TEPP-46 or by global PKM2 knockout in mice, highlighting the essential function of PKM2 in lipid metabolism. Although depletion of PKM2 decreases cancer cell growth, global PKM2 knockout accelerates allografted tumor growth. Together, our findings reveal the cell-autonomous and systemic effects of PKM2 in lipid homeostasis and carcinogenesis, as well as TMEM33 as a bona fide regulator of lipid metabolism.

| S-EPMC8591543 | biostudies-literature

PKM2-TMEM33 axis regulates lipid homeostasis in cancer cells by controling SCAP stability

Project description:Purpose: The goals of this study are to investigate the effect of PKM2 KO or TMEM33 overexpression on genes expression. Methods: Fresh PKM2 KO MCF7, PKM2 KO MDA-MB-231 and TMEM33 OE MDA-MB-231 cell pellets, and their respective parental cells, were used for RNA extraction. RNA sequencing libraries were prepared using the Illumina TruSeq RNA Library Prep Kit v2 following the manufacturer’s instructions. Each library was sequenced in single read mode, 1 x 50 bp, using the HiSeq4000 platform. Sequencing reads were aligned to human genome (hg38) by STAR (version 2.5.2b). Expression levels of genes annotated in GENCODE (version 24 for PKM2 KO and their parental cells; version 27 for TMEM33 OE and their control cells) were quantified by RSEM (version 1.3.0). Parameters of STAR and RSEM were set following ENCODE’s long RNA-seq processing pipeline. Differentially expressed genes were identified by DESeq2 (version 1.24.0) under the requirement of at least two-fold changes and an adjusted p-value < 0.05. Results: Differential gene expression analyses identified 269 and 504 significantly up-regulated and 204 and 289 significantly down-regulated genes in MDA-MB-231 and MCF7 PKM2 KO cells compared to their parental cells (>=2-fold, adjusted P value < 0.05); Gene set enrichment analysis (GSEA) showed that cholesterol homeostasis and fatty acid metabolism were among the top down-regulated pathways in MDA-MB-231 TMEM33 OE cells. Moreover, the differential gene expression profiles between PKM2 KO and TMEM33 OE cell lines were positively correlated. Notably, the mRNAs of genes related to cholesterol homeostasis were decreased in both PKM2 KO and TMEM33 OE cells. Conclusions: TMEM33 acts as a downstream effector of PKM2 that regulates activation of SREBPs and lipid metabolism.

2021-08-06 | GSE175956 | GEO

PKM2-TMEM33 axis regulates lipid homeostasis in cancer cells by controling SCAP stability

Project description:PKM2-TMEM33 axis regulates lipid homeostasis in cancer cells by controling SCAP stability

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