Page 74 - GPD-3-2

Gene & Protein in Disease Opportunities and challenges of HIF-1 in cancer

pathways support this observation. 56,57 Significant metrics requires HIF-1 binding for its release. One particular
include the presence and levels of RhoA and RhoC and study on breast cancer cells used ChIP-qPCR and RNA-
their relationship during the cell cycle and the lifecycle sequencing to demonstrate that HIF-1 mobilizes TRIM28
of the neoplasm. Complementary to the above stands, and DNA-dependent protein kinase (DNA-PK) to HREs to
HIF-1α alters the architecture of the cytoskeleton through release the stalled Pol II and enable effective transcription.
the regulation of Rho kinase, which, in turn, further The increased expression of HIF-1, DNA-PKcs, or
stabilizes HIF-1α in a positive feedback loop, as evidenced TRIM28 in different types of human cancer is associated
by the accumulation of the latter. 57,58 Concerning blood with increased patient mortality. Thus, inhibition of HIF-
69
supply, HIF-1α reorganizes the cytoskeletal structure of dependent transcription may partially contribute to the
endothelial, parenchymal, and immune cells, resulting anticancer effects of drugs targeting DNA-PK in breast
in morphologies that favor intracellular adhesion and cancer.
increase vascularization, which leads to proliferation A recent study demonstrated that hypoxia-inducible
and higher metastatic potential. Considering the above, gene expression in estrogen receptor (ER)-positive
59
it is unsurprising that elevated RhoC levels serve as an MCF7 and ER-negative SUM159 human breast cancer
unfavorable prognostic factor. 57
cells requires the presence of the histone H2A/H2B
Another aspect of EMT is the emergence of stem-like chaperone facilitates chromatin transcription (FACT),
characteristics in a subset of cancer cells, which promotes and the H2B ubiquitin ligase RING finger protein
tumorigenesis, facilitates metastasis, and leads to poor 20/40 (RNF20/40). Hypoxic conditions provoke the
treatment outcomes. HIF-1, as a mediator in EMT, accumulation of HIF-1α, its translocation to the nucleus,
60
increases the population of stem-like cells in thyroid subsequent heterodimerization with HIF-1β, binding
61
and prostate cancer, and plays a key role in promoting to HREs in target genes, and recruitment of FACT and
62
mammary tumor growth and metastasis. 63 RNF20/40. The creation of this HIF-1-FACT-RNF20/40
Pancreatic cancer metastasis is facilitated by EMT, and multiprotein complex produces several consequences. Due
one particular study examined the influence of intermittent to protein-protein interactions, each protein contributes
hypoxia on the invasiveness of human pancreatic cancer to a stabilized occupancy of the HRE by the other two.
cell lines (Panc-1 and BxPC-3). Western blotting and H2B-K120 ubiquitination by RNF20/40 facilitates the
flow cytometry analysis were used to quantify stem-like FACT-dependent displacement of an H2A-H2B dimer
cells in the migratory cells during intermittent hypoxia from nucleosomes, promoting the release of stalled RNA
in these human pancreatic cancer cells. Under normoxia Pol II and enhancing transcriptional elongation. RNA-
or intermittent hypoxia, the expression of autophagy- sequencing data showed that FACT and RNF20/40 are
related proteins (LC3-II and Beclin), HIF-1, and EMT- required to regulate the expression of virtually all hypoxia-
related markers (E-cadherin, vimentin, and N-cadherin) responsive RNAs in MCF7 breast cancer cells, providing
was examined using Western blotting. The study showed the basis for increased rates of transcription initiation and
70
that under intermittent hypoxia, pancreatic cancer cells elongation. HIF-1, FACT, and RNF20/40 are all elevated
demonstrated enhanced invasiveness and enriched stem- in breast cancer and are linked with increased patient
71
like cells. Increased levels of HIF-1 upregulated autophagy mortality. Therefore, suppressing their activity could be
and both were associated with the metastatic ability and a potential therapeutic approach in cases of triple-negative
EMT of pancreatic CSCs. 64 breast cancers, for which targeted therapy is currently
unavailable.
Chronic hypoxia raises the levels of intracellular
reactive oxygen species (ROS), which are crucial for 2.3. Factors regulating HIF-1
65
tumorigenesis and metastasis. ROS stabilize HIF-1 During normoxia, specific proline residues of HIF-1α,
through a redox-mediated inhibition of its proteolysis and namely, P402 and P564, are hydroxylated by PHDs. This
66
triggers its downstream pathways. The signaling cascade modification causes the ubiquitination of HIF-1α by the
ROS/STAT3/HIF-1α/TWIST1/N-cadherin is implicated von Hippel-Lindau (VHL)-containing E3 ubiquitin ligase
in prostate cancer progression. In addition, ROS and and subsequent HIF-1α degradation. Under hypoxic
67
HIF-1 induce resistance to doxorubicin and etoposide in conditions, these oxygen-dependent hydroxylases become
lung, cervical carcinoma, and melanoma cell lines. 68 inactive, allowing the formation of HIF-1 heterodimer
72
As a key contributor in cell adaptation to hypoxia, through the interaction between HIF-1α and HIF-1β.
HIF-1 influences target gene transcription through This heterodimer binds to HRE, triggering the expression
RNA polymerase II (Pol II), but this enzyme stalls after of many genes, including VEGF and platelet-derived
transcribing approximately 30 – 60 nucleotides and growth factor-B (PDGFB). Clinical research has shown a

Volume 3 Issue 2 (2024) 7 doi: 10.36922/gpd.3431