D-lactate induces lysine D-lactylation to regulate transcription
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Kai Zhang
PROVIDER: PXD053161 | iProX | Sat Jun 15 00:00:00 BST 2024
REPOSITORIES: iProX
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Project description:Hypoxia promotes tumorigenesis and lactate accumulation in esophageal squamous cell carcinoma (ESCC). Lactate can induce histone lysine lactylation (Kla, a recently-identified histone marks) to regulate transcription. However, the functional consequence of histone Kla under hypoxia in ESCC remains to be explored. Here, we reveal that hypoxia facilitates histone H3K9la to enhance LAMC2 transcription for proliferation of ESCC. We found that global level of Kla was elevated under hypoxia, and thus identified the landscape of histone Kla in ESCC by quantitative proteomics. Furthermore, we show a significant increase of H3K9la level induced by hypoxia. Next, MNseq ChIP-seq and RNA-seq analysis suggest that H3K9la is enriched at the promoter of cell junction genes. Finally, we demonstrate that the histone H3K9la facilitates the expression of LAMC2 for ESCC invasion by in vivo and in vitro experiments. Briefly, our study reveal a vital role of histone Kla triggered by hypoxia in cancer.
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Project description:The recently identified histone modification lysine lactylation can be stimulated by L-lactate and glycolysis. Although the chemical group added upon lysine lactylation was originally proposed to be the L-enantiomer of lactate (KL-la), two isomeric modifications, lysine D-lactylation (KD-la), and N-ε-(carboxyethyl) lysine (Kce), also exist in cells, with their precursors being metabolites of glycolysis. The dynamic regulation and differences among these three modifications in response to hypoxia have not been investigated previously. In this study, we demonstrate that intracellular KL-la, but not KD-la or Kce, is upregulated in response to hypoxia. Depletion of glyoxalase enzymes, GLO1 and GLO2, had minimal impact on KD_x001E_la, Kce, or hypoxia-induced KL-la. Conversely, blocking glycolytic flux to L-lactate under hypoxic conditions by knocking out LDHA/B completely abolished the induction of KL-la, but increased KD-la and Kce. We further observed a correlation between the level of KL-la and HIF-1α expression under hypoxic conditions and when small molecules were used to stabilize HIF-1α in the normoxia condition. Our result demonstrated that there is a strong correlation between HIF-1α and KL-la in lung cancer tissues, and that patient samples with higher grade tend to have higher KL-la levels. Using a proteomics approach, we quantified 66 KL-la sites that were upregulated by hypoxia and demonstrated that p300/CBP contributes to hypoxia-induced KL-la. Collectively, our study demonstrates that KL-la, rather than KD-la or Kce, is the prevailing lysine lactylation in response to hypoxia. Our results therefore demonstrate a link between KL-la and the hypoxia-induced adaptation of tumor cells.
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Project description:Lysine lactylation (Kla) is a new type of histone mark implicated in the regulation of various functional processes such as transcription. However, how this histone mark acts in cancers remains unexplored due in part to a lack of knowledge about its reader proteins. Here, we observe that cervical cancer (CC) cells undergo metabolic reprogram by which lactate accumulation and thereby boost histone lactylation, particularly H3K14la. Utilizing a multivalent photoaffinity probe in combination with quantitative proteomics approach, we identify DPF2 as a candidate target of H3K14la. Biochemical studies as well as CUT&Tag analysis reveal that DPF2 is capable of binding to H3K14la, and co-localizes with it on promoters of oncogenic genes. Notably, disrupting the association between DPF2 and histone lactylation through structure-guided mutation blunts those cancer-related gene expression along with cell survival. Together, our findings reveal DPF2 as a bona fide H3K14la effector that couples histone lactylation to gene transcription and cell survival, offering insight into how histone Kla engages in transcription and tumorigenesis.
2024-06-17 | GSE267107 | GEO
Project description:Lysine lactylation (Kla) is a new type of histone mark implicated in the regulation of various functional processes such as transcription. However, how this histone mark acts in cancers remains unexplored due in part to a lack of knowledge about its reader proteins. Here, we observe that cervical cancer (CC) cells undergo metabolic reprogram by which lactate accumulation and thereby boost histone lactylation, particularly H3K14la. Utilizing a multivalent photoaffinity probe in combination with quantitative proteomics approach, we identify DPF2 as a candidate target of H3K14la. Biochemical studies as well as CUT&Tag analysis reveal that DPF2 is capable of binding to H3K14la, and co-localizes with it on promoters of oncogenic genes. Notably, disrupting the association between DPF2 and histone lactylation through structure-guided mutation blunts those cancer-related gene expression along with cell survival. Together, our findings reveal DPF2 as a bona fide H3K14la effector that couples histone lactylation to gene transcription and cell survival, offering insight into how histone Kla engages in transcription and tumorigenesis.
2024-06-17 | GSE267109 | GEO
Project description:Lysine lactylation (Kla), is a newly found post-translational modification that has been found to be involved in the pathogenesis of many diseases. However, the specific effect of protein lactylation has not been reported on the development of diabetic cardiomyopathy (DCM). Here, the purpose of this study was determined whether protein lactylation was involved in the progression of DCM. LC-MS/MS was used to perform proteomic and lactate analysis on the heart tissues of db/m mice (Control group) and db/db mice (DCM group). Subsequently, a series of bioinformatics analyses were used to analyze the kla site and Kla modified proteins in two groups, including GO enrichment, KEGG enrichment, LASSO regression, Logistic regression, random forest (RF), VM-Recursive Feature Elimination (SVM-RFE) algorithm, and other analysis methods. The bioinformatics data analysis showed that the Kla sites in the DCM group were more than those in the Control group. In addition, subcellular localization analysis showed that Kla modified proteins were mainly located in mitochondria and cytoplasm. The protein lactylated modification mainly occurred on histone H2, and compared with the Control group, the modification of H4C1-K32 sites was significantly higher in the DCM group. Furthermore, there were 113 significantly modified kla sites corresponding to 78 modified proteins in the DCM group, while there were 37 significantly modified kla sites corresponding to 25 modified proteins in the Control group. These Kla modified proteins were involved in biological processes and pathways related to glucose metabolism and DCM. Finally, five kla sites were selected as candidate sites by using four machine learning methods, namely A2ASS6 _ K928 _ Ttn, A2ASS6 _ K13499 _ Ttn, Q61425 _ K212 _ Hadh, Q8K2B3 _ K517 _ Sdha, and Q9R0Y5 _ K100 _ Ak1. In conclusions, the present study first reported on the combination of lactylome and proteome of DCM, providing a reliable basis for further investigating the roles of Kla and Kla modified proteins in DCM.
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