Abstract
Simple SummaryHepatocellular carcinoma (HCC) is one of the deadliest human health burdens worldwide. However, the molecular mechanism of HCC development is still not fully understood. Sex determining region Y-related high-mobility group box (SOX) transcription factors not only play pivotal roles in cell fate decisions during development but also participate in the initiation and progression of cancer. Given the significance of SOX factors in cancer and their ‘undruggable’ properties, we summarize the role and molecular mechanism of SOX family members in HCC and the regulatory effect of SOX factors in the tumor immune microenvironment (TIME) of various cancers. For the first time, we analyze the association between the levels of SOX factors and that of immune components in HCC, providing clues to the pivotal role of SOX factors in the TIME of HCC. We also discuss the opportunities and challenges of targeting SOX factors for cancer.Sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) factors belong to an evolutionarily conserved family of transcription factors that play essential roles in cell fate decisions involving numerous developmental processes. In recent years, the significance of SOX factors in the initiation and progression of cancers has been gradually revealed, and they act as potential therapeutic targets for cancer. However, the research involving SOX factors is still preliminary, given that their effects in some leading-edge fields such as tumor immune microenvironment (TIME) remain obscure. More importantly, as a class of ‘undruggable’ molecules, targeting SOX factors still face considerable challenges in achieving clinical translation. Here, we mainly focus on the roles and regulatory mechanisms of SOX family members in hepatocellular carcinoma (HCC), one of the fatal human health burdens worldwide. We then detail the role of SOX members in remodeling TIME and analyze the association between SOX members and immune components in HCC for the first time. In addition, we emphasize several alternative strategies involved in the translational advances of SOX members in cancer. Finally, we discuss the alternative strategies of targeting SOX family for cancer and propose the opportunities and challenges they face based on the current accumulated studies and our understanding.
Highlights
Transcription factors (TFs) are one of the most pivotal sequence-specific DNA-binding proteins responsible for decoding DNA sequences
In order to accomplish the transcriptional regulation of genes, TFs require at least one DNA-binding domain (DBD) for recognizing and binding specific DNA sites located in promoters or enhancers/silencers of targeted genes and another effector domain for recruiting transcriptional machinery to DNA [1]
SOX9 binds to the enhancer of INHBB and induces its expression, thereby increasing the secretion of activin B from hepatocellular carcinoma (HCC) cells into the microenvironment, leading to the activation of peri-tumoral Hepatic stellate cells (HSCs) mediated by activin B/Smad signaling and subsequently promoting liver fibrosis and metastasis of HCC [108]
Summary
Transcription factors (TFs) are one of the most pivotal sequence-specific DNA-binding proteins responsible for decoding DNA sequences. In order to accomplish the transcriptional regulation of genes, TFs require at least one DNA-binding domain (DBD) for recognizing and binding specific DNA sites located in promoters or enhancers/silencers of targeted genes and another effector domain for recruiting transcriptional machinery to DNA [1] To this point, over 2000 TFs divided into various families based on the homologous DBDs have been identified, many of which enable the controlling of some critical biological processes in a way that depends on cell type and development patterning [2]. The genes encoding TFs produce fusion proteins with functional alteration due to frequent chromosomal translocations such as PLZF-RARα [5] These abnormal TFs fusion products disrupt the transcriptional networks during the specific periods of hematopoietic cell differentiation and cause the initiation of cancer [5]. We emphasize several alternative strategies involved in the translational advances of SOX members in cancer, and discuss the opportunities and challenges of targeting the SOX family in cancer based on the current accumulated studies and on our understanding
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