Hypoxia activated long non-coding RNA HABON regulates the growth and proliferation of hepatocarcinoma cells by binding to and antagonizing HIF-1 alpha

Abstract

The adaptation of tumour cells to hypoxic microenvironment is one of the most significant characteristics of many malignant tumour diseases including hepatocarcinoma. Recently, long non-coding RNAs (lncRNAs) have been reported to play important roles in the various levels of gene regulation thus functioning in growth and survival of tumour cells. Here, new hypoxia-related lncRNAs in hepatocarcinoma cells were screened and validated by lncRNA chip-array as well as real-time RT-PCR. Among them, a hypoxia-activated lncRNA that we identified and termed Hypoxia-Activated BNIP3 Overlapping Noncoding RNA (HABON), was not only regulated by hypoxic-induced factor-1α (HIF-1α) but its expression increased significantly under hypoxia in tumour cells. We deciphered the biological characteristics of HABON including its cell localization, genomic location, as well as its full-length sequence, and proved HABON could promote growth, proliferation and clone-formation of hepatocarcinoma cells under hypoxia. Then, we revealed that HABON was transcriptionally activated by HIF-1α in hypoxic cells, furthermore, it could interact with HIF-1α and promote its protein degradation, thus affecting transcription of HIF-1α's target genes to exert its effects on cells. Besides, the elevated expression of HABON under hypoxia could promote the transcriptional activation of BNIP3 through HIF-1α, and increasing the expression level of BNIP3. This research provides a novel clue for the adaptive survival and growth mechanism of tumour under hypoxia, and gives a way to reveal the nature of tumour cells' resistance characteristics to harsh microenvironment.

Identification and Validation of Hypoxia-Related lncRNA Signature as a Prognostic Model for Hepatocellular Carcinoma

“…LncRNA SNHG11 promotes invasion and metastasis of colorectal cancer cells by regulating HIF-1α ( Xu et al, 2020b ). Hypoxia activated lncRNA HABON enhances the proliferation and growth of hepatocarcinoma cells by mediating HIF-1α ( Ma et al, 2021 ). Hypoxia-inducible miR-182 accelerates tumor angiogenesis and growth by regulating the expression level of HIF1α in prostate cancer cells ( Li et al, 2015 ).…”

Mechanisms of Hepatocarcinogenesis Development in an Acidic Microenvironment

“…can be transcriptionally regulated by HIF-1 and regulate the energy production of cancer cells to maintain their proliferation and survival [22]. It has been reported [23][24][25][26] that lactic acid production from of liver cancer cells can be amplified by HIF-1, which results in altering the activity of enzymes associated with glycolysis that lead to microenvironment acidification of liver cancer tissues. This inhibition can affect the growth and proliferation of liver cancer by regulating the energy metabolism.…”

An Effective Hypoxia-Related Long Non-Coding RNA Assessment Model for Prognosis of Lung Adenocarcinoma

“…According to the study, many lncRNAs play a regulatory role in the hypoxia of tumors, such as participating in the regulation of tumor growth, vascular formation, invasion, and metastasis. Under hypoxic conditions, the lncRNA HABON could promote growth and proliferation of hepatocarcinoma cells ( Ma C et al, 2021 ; Ma T et al, 2021 ). In the hypoxic environment of gastric cancer, the expression of the lncRNA LINC00460 is upregulated and promotes tumor invasiveness ( Chen et al, 2020 ).…”