Dataset Information

HOXA9 Transcriptionally Promotes Apoptosis and Represses Autophagy by Targeting NF-?B in Cutaneous Squamous Cell Carcinoma.

ABSTRACT: Tumor suppressor HOXA9 has been identified to promote apoptosis in cutaneous squamous cell carcinoma (cSCC). However, the mechanism of such pro-apoptotic role of HOXA9 remains obscure. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis of RNA-seq data showed that NF-?B, apoptosis and autophagy pathways are significantly regulated after HOXA9 knockdown. HOXA9 transcriptionally regulates RELA, the p65 subunit of NF-?B. Loss of HOXA9 in cSCC significantly upregulates RELA expression and thus enhances NF-?B pathway. Interestingly, RELA transcriptionally promotes not only anti-apoptotic factor BCL-XL but also autophagic genes including ATG1, ATG3, and ATG12. Our results reveal an enhanced NF-?B signaling network regulated by HOXA9, which contributes to repressed apoptosis and activated autophagy in cSCC development and may represent an intervention target for cSCC therapy.

SUBMITTER: Han S

PROVIDER: S-EPMC6912505 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

HOXA9 Transcriptionally Promotes Apoptosis and Represses Autophagy by Targeting NF-κB in Cutaneous Squamous Cell Carcinoma.

Han Shuo S Li Xue X Liang Xiaoting X Zhou Liang L

Cells 20191031 11

Tumor suppressor HOXA9 has been identified to promote apoptosis in cutaneous squamous cell carcinoma (cSCC). However, the mechanism of such pro-apoptotic role of HOXA9 remains obscure. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis of RNA-seq data showed that NF-κB, apoptosis and autophagy pathways are significantly regulated after HOXA9 knockdown. HOXA9 transcriptionally regulates RELA, the p65 subunit of NF-κB. Loss of HOXA9 in cSCC significantly upregulates RELA expression and thus e ...[more]

PMID: 31683603

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Project description:C/EBPα plays a key role in specifying myeloid lineage development. HoxA9 is expressed in myeloid progenitors, with its level diminishing during myeloid maturation, and HOXA9 is over-expressed in a majority of acute myeloid leukemia cases, including those expressing NUP98-HOXD13. The objective of this study was to determine whether HoxA9 directly represses Cebpa gene expression. We find 4-fold increased HoxA9 and 5-fold reduced Cebpa in marrow common myeloid and LSK progenitors from Vav-NUP98-HOXD13 transgenic mice. Conversely, HoxA9 decreases 5-fold while Cebpa increases during granulocytic differentiation of 32Dcl3 myeloid cells. Activation of exogenous HoxA9-ER in 32Dcl3 cells reduces Cebpa mRNA even in the presence of cycloheximide, suggesting direct repression. Cebpa transcription in murine myeloid cells is regulated by a hematopoietic-specific +37 kb enhancer and by a more widely active +8 kb enhancer. ChIP-Seq analysis of primary myeloid progenitor cells expressing exogenous HoxA9 or HoxA9-ER demonstrates that HoxA9 localizes to both the +8 kb and +37 kb Cebpa enhancers. Gel shift analysis demonstrates HoxA9 binding to three consensus sites in the +8 kb enhancer, but no affinity for the single near-consensus site present in the +37 kb enhancer. Activity of a Cebpa +8 kb enhancer/promoter-luciferase reporter in 32Dcl3 or MOLM14 myeloid cells is increased ~2-fold by mutation of its three HOXA9-binding sites, suggesting that endogenous HoxA9 represses +8 kb Cebpa enhancer activity. In contrast, mutation of five C/EBPα-binding sites in the +8 kb enhancer reduces activity 3-fold. Finally, expression of a +37 kb enhancer/promoter-hCD4 transgene reporter is reduced ~2-fold in marrow common myeloid progenitors when the Vav-NUP98-HOXD13 transgene is introduced. Overall, these data support the conclusion that HoxA9 represses Cebpa expression, at least in part via inhibition of its +8 kb enhancer, potentially allowing normal myeloid progenitors to maintain immaturity and contributing to the pathogenesis of acute myeloid leukemia associated with increased HOXA9.

Dataset Information

HOXA9 Transcriptionally Promotes Apoptosis and Represses Autophagy by Targeting NF-?B in Cutaneous Squamous Cell Carcinoma.

Publications

HOXA9 Transcriptionally Promotes Apoptosis and Represses Autophagy by Targeting NF-κB in Cutaneous Squamous Cell Carcinoma.

Similar Datasets

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