Expression signatures of HOX cluster genes in cervical cancer pathogenesis: Impact of human papillomavirus type 16 oncoprotein E7

Abstract

The Homeobox (HOX) genes encode important transcription factors showing deregulated expression in several cancers. However, their role in cervical cancer pathogenesis, remains largely unexplored. Herein, we studied their association with Human Papillomavirus type 16 (HPV16) mediated cervical cancers. Our previously published gene expression microarray data revealed a significant alteration of 12 out of 39 HOX cluster members among cervical cancer cases, in comparison to the histopathologically normal controls. Of these, we validated seven (HOXA10, HOXA13, HOXB13, HOXC8, HOXC9, HOXC11 and HOXD10) by quantitative real-time PCR. We identified decreased HOXA10 expression as opposed to the increased expression of the rest. Such decrease was independent of the integration status of HPV16 genome, but correlated negatively with E7 expression in clinical samples, that was confirmed in vitro. HOXA10 and HOXB13 revealed association with Epithelial-Mesenchymal Transition (EMT). While HOXA10 expression correlated positively with E-Cadherin and negatively with Vimentin expression, HOXB13 showed the reverse trend. Chromatin immunoprecipitation study in vitro revealed the ability of E7 to increase HOX gene expression by epigenetic regulation, affecting the H3K4me3 and H3K27me3 status of their promoters, resulting from a loss of PRC2-LSD1 complex activity. Thus, besides identifying the deregulated expression of HOX cluster members in HPV16 positive cervical cancer and their association with EMT, our study highlighted the mechanism of HPV16 E7-mediated epigenetic regulation of HOX genes in such cancers, potentially serving as bedrock for functional studies in the future.

Long Non-coding RNA DLEU1 Promotes Proliferation and Invasion by Interacting With miR-381 and Enhancing HOXA13 Expression in Cervical Cancer

“…HOXA13 has been reported to be upregulated and has been demonstrated to play an oncogenic role in tumorigenesis and progression in various tumors (Dong Y. et al, 2017 He et al, 2017). Although HOXA13 was highly expressed in CC tissues compared to normal cervical tissues (Saha et al, 2017), its role in the proliferation and invasion of CC cells has not been reported. Through the bioinformatic analysis, we predicted the potential miRNA binding site in HOXA13.…”

Epigenomic profiling of DNA methylation for hepatocellular carcinoma diagnosis and prognosis prediction

“…HOX genes are a family of transcription factors that show deregulated expression in a variety of cancers . Saha reported that HOXA10 and HOXB13 were associated with the process of epithelial–mesenchymal transition in cervical cancer . Aberrant expression of HOX cluster genes is integral to a network of regulatory mechanisms involved in normal adult tissue homeostasis, and maintenance and activation of stem cell self‐renewal process, crucial to malignant transformation .…”

“…[25][26][27] Saha reported that HOXA10 and HOXB13 were associated with the process of epithelial-mesenchymal transition in cervical cancer. 28 Aberrant expression of HOX cluster genes is integral to a network of regulatory mechanisms involved in normal adult tissue homeostasis, and maintenance and activation of stem cell self-renewal process, crucial to malignant transformation. [29][30][31] Our methylation profile revealed that hypermethylation of the HOX cluster member genes may play an important role in the carcinogenesis of HCC.…”

Upregulation of homeobox gene is correlated with poor survival outcomes in cervical cancer

“…Aberrant expression of HOXD9 , HOXC5 , HOXC8 , and HOXB2, HOXB4, HOXC10 , and HOXD13 has been found in cervical cancer cell lines [ 11 – 13 ]. A recent study focused on the mechanism of HPV16 E7-mediated epigenetic regulation of HOX genes showed the master regulatory role of HPV16 E7 in modulating the expression of HOX cluster genes [ 14 ]. Several studies have also revealed the potential roles of HOX antisense long non-coding RNAs in cervical cancer aggressiveness [ 15 – 17 ].…”