Background
Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancers and is a highly aggressive malignancy characterized by high mortality and poor prognosis. Despite significant advances in surgical resection, local therapies, targeted therapy, and immunotherapy, the overall survival rate of HCC patients remains unsatisfactory. Therefore, elucidating the key molecular mechanisms driving HCC progression and identifying molecular biomarkers for early diagnosis and prognosis assessment are imperative for the development of more effective therapeutic strategies.
Hypoxia is a hallmark of the tumor microenvironment in HCC and serves as a critical driver of malignant progression and unfavorable prognosis. The hypoxia-inducible factor HIF-1α, a central transcriptional regulator of cellular responses to hypoxia, is primarily regulated through the VHL-mediated ubiquitin-proteasome pathway. In HCC patients with poor prognosis, aberrant stabilization and activation of HIF-1α are frequently observed, which in turn promotes tumor progression by transcriptionally upregulating genes involved in angiogenesis, metabolic reprogramming, and metastasis, making HIF-1α a key therapeutic target in HCC. However, the specific regulatory mechanisms by which hypoxia promotes HCC progression, as well as the complex network underlying the abnormal activation of HIF-1α, have not yet been fully elucidated.
Research Progress
Recently, a collaboration between the team of Prof. Dongsheng Huang, Prof. Qiuran Xu, and Dr. Di Cui from Zhejiang Provincial People’s Hospital, and the team of Prof. Kangsheng Tu from the First Affiliated Hospital of Xi’an Jiaotong University revealed that the ubiquitin conjugation enzyme E2 variant 1 (UBE2V1) forms a positive feedback loop with hypoxia-inducible factor-1α to promote HCC progression.
The researchers identified UBE2V1 as a novel hypoxia-responsive gene that is transcriptionally activated by HIF-1α through direct binding to a hypoxia-response element located between −208 and −201 bp in the UBE2V1 promoter. Overexpression of UBE2V1 was frequently detected in HCC tissues and correlates strongly with advanced tumor stage and unfavorable patient prognosis. Moreover, UBE2V1 facilitated the proliferation and migration of HCC cells. Further investigation revealed that up-regulated UBE2V1 competes with HIF-1α for binding to the β-domain of VHL protein and, in complex with UBE2S, catalyzes K11/K48-linked ubiquitination at VHL K196, leading to its proteasomal degradation. This disruption of VHL function attenuates HIF-1α ubiquitination and degradation, resulting in sustained HIF-1α stabilization, increased nuclear accumulation, and enhanced transcriptional activity. Consistent with these findings, genetic knockdown of UBE2V1 or pharmacological inhibition of HIF-1α markedly suppress HCC tumorigenesis and metastasis in vivo.
Future Prospects
This study reveals a previously unrecognized, self-reinforcing positive feedback loop involving HIF-1α and UBE2V1 (Fig. 1). This loop plays a critical role in maintaining the hypoxic tumor microenvironment and driving the progression of HCC. The findings not only deepen our understanding of the molecular mechanisms underlying HCC progression but also provide a mechanistic foundation for developing novel therapeutic strategies targeting the UBE2V1-HIF-1α axis. Future translational research should further evaluate the clinical potential of this pathway as both a prognostic biomarker and a therapeutic target, aiming at improving outcomes for HCC patients.
The complete study is accessible via DOI: 10.34133/research.1041