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

Shuo Han; Xue Li; Xiaoting Liang; Liang Zhou

doi:10.3390/cells8111360

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

Cells. 2019 Oct 31;8(11):1360. doi: 10.3390/cells8111360.

Authors

Shuo Han¹, Xue Li², Xiaoting Liang³, Liang Zhou⁴

Affiliations

¹ Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangdong 510515, Guangzhou, China. [email protected].
² Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangdong 510515, Guangzhou, China. [email protected].
³ Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangdong 510515, Guangzhou, China. [email protected].
⁴ Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangdong 510515, Guangzhou, China. [email protected].

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-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 enhances NF-κB 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-κB 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.

Keywords: HOXA9; NF-κB; apoptosis; autophagy; cutaneous squamous cell carcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis*
Autophagy*
Autophagy-Related Protein-1 Homolog / genetics
Autophagy-Related Protein-1 Homolog / metabolism
Carcinoma, Squamous Cell / drug therapy
Carcinoma, Squamous Cell / metabolism
Carcinoma, Squamous Cell / pathology
Cell Line, Tumor
Homeodomain Proteins / antagonists & inhibitors
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Male
Mice
Mice, Nude
RNA Interference
RNA, Small Interfering / metabolism
RNA, Small Interfering / therapeutic use
Signal Transduction
Skin Neoplasms / drug therapy
Skin Neoplasms / metabolism
Skin Neoplasms / pathology
Transcription Factor RelA / genetics
Transcription Factor RelA / metabolism*
Transplantation, Heterologous
Up-Regulation
bcl-X Protein / genetics
bcl-X Protein / metabolism

Substances

Homeodomain Proteins
Intracellular Signaling Peptides and Proteins
RELA protein, human
RNA, Small Interfering
Transcription Factor RelA
bcl-X Protein
homeobox protein HOXA9
Autophagy-Related Protein-1 Homolog
ULK1 protein, human