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Can Targeting the HMGB1/SET/HAT1-SASH1 Axis Prevent Lung Cancer Progression?

By Stuart P. Atkinson, Ph.D.

October 20, 2025

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How Do Cancer Cell Metabolites Promote DNA Repair and Cell Survival?

The high-mobility group box 1 (HMGB1) protein coordinates cell stress responses and generally functions as a cellular “guardian” (Kang et al.); additionally, HMGB1 participates in the epigenetic regulation of gene expression by influencing the structure and stability of chromatin and regulating the accessibility of gene regulatory elements (Andersson et al. and Wu & Yang). A review from researchers led by Lili Yang (Tianjin Medical University) recently summarized the known links between HMGB1 overexpression and tumorigenesis/disease progression (Wu & Yang), while a related study reporting HMGB1 as a positive regulator of glutamine metabolism in hepatocellular carcinoma (Wei et al.) suggested a possible role for HMGB1 in regulating tumor metabolism (glycolysis) and promoting metastasis.

A recent study from the Yang lab aimed to elucidate the specific functions/mechanisms of HMGB1 in regulating glycolysis during the progression of lung adenocarcinoma (LUAD), a common cancer often detected for the first time at the metastatic stage (Popper, 2016). LUAD development to this aggressive, resistant tumor stage requires the dysregulation of tumor oncogenes and metabolic alterations (Chen et al., Perlikos et al., and Vander Heiden & DeBerardinis), with the latter linked to changes at the epigenetic level (Johnson et al.).

The team now describes their most recent results in an Oncogene article, which reveals how elevated HMGB1 expression levels in LUAD may promote tumor cell proliferation and metastasis by via metabolic reprogramming in a mechanisms that involves the attenuation of H3K9 and H3K27 acetylation levels at the SASH1 gene loci via physical interactions with the SET nuclear proto-oncogene and the HAT1 (KAT1) histone acetyltransferase (Kou et al.).

Does this newly discovered HMGB1/SET/HAT1-SASH1 axis provide an epigenetic link to altered tumor cell metabolism and metastasis in aggressive lung cancer cases?

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Identifying HMGB1/SET/HAT1-SASH1 as a Targetable Axis in Lung Cancer

An initial comparison of LUAD patient samples and adjacent healthy tissues revealed tumor-associated HMGB1 overexpression, which positively correlated with disease relapse, lymph node metastasis, disease stage, higher recurrence risk, and shortened lifespan. In parallel, in vitro studies demonstrated how HMGB1 loss in lung cancer cell lines significantly inhibited their invasive capacity and reduced levels of cellular glycolysis.

The authors next identified interacting proteins to explore how HMGB1 loss potentially affected glycolysis and metastasis in LUAD, revealing that HMGB1 interacted with SET, an oncoprotein involved in apoptosis, transcription, nucleosome assembly/histone chaperoning, and the inhibition of histone acetylation (Lu et al., Saavedra et al., and Seo et al.). Furthermore, they discovered that SET interacted with HAT1 (or KAT1), which mediates the acetylation of lysine residues on histone H4 and H3 (Yang et al.). Subsequent analysis revealed the colocalization of HMGB1, SET, and HAT1 in LUAD cell nuclei and suggested that SET and HAT1 impacted HMGB1 binding to target genes and that HMGB1 functioned to inhibit HAT1-mediated acetylation of H3K9 and H3K27 by interacting with SET. In summary, these data revealed that a HMGB1/SET/HAT1 complex may influence LUAD progression/aggressiveness in part by regulating H3K9ac and H3K27ac levels.

The identification of transcriptional targets of the HMGB1/SET/HAT1 complex employed ChIP-sequencing in lung cancer cell lines; in summary, the team discovered 368 regions displaying overlapping HMGB1/SET binding and highlighted how the overrepresentation of cell adhesion-related genes associated with said regions suggested the involvement of the HMGB1/SET/HAT1 complex in regulating cancer metastasis at a transcriptional level. A literature review helped prioritize six genes associated with the 368 regions: SASH1, KAT6B, MBNL2, SEMA3A, SPRY, and PDZD2. The expression of the SASH1 tumor suppressor gene becomes suppressed in cancers such as LUAD (Burgess et al.); here, the authors posited a role for SASH1 in metabolism and revealed that HMGB1, SET, and HAT1 all co-bound the SASH1 gene promoter region to repress expression in lung cancer cell lines; however, HMGB1 or SET loss or HAT overexpression prompted an increase in H3K9ac and H3K27ac levels at the SASH1 promoter region and SASH1 expression. Collectively, these data indicate that increased levels of HMGB1 in LUAD lead to the loss of histone acetylation at the SASH1 gene promoter and the loss of SASH1 gene expression.

The authors next evaluated glucose uptake and metastasis in lung cancer cell lines after knocking down HMGB1, SET, and HAT1; these experiments provided further evidence that the HMGB1/SET/HAT1 complex regulated glycolysis (altering lactate production, glucose uptake, and ATP production) and, as tumor metastasis depends largely on glycolysis for energy production (Abdel-Wahab et al.), mediated tumor metastasis by inhibiting SASH1 expression. Encouragingly, further exploration of the role of HMGB1 in glycolysis and metastasis of lung cancer cell-mediated tumor growth in vivo indicated that HMGB1 loss in tumor tissues suppressed metastasis and glycolysis by epigenetically promoting SASH1 gene expression via HAT1.

Finally, the authors turned to LUAD samples to explore the role of HMGB1/SET/HAT1-SASH1 in disease progression, which again provided evidence for the involvement of this axis in glycolysis; furthermore, stratifying LUAD patients into groups according to HMGB1 or SASH1 expression revealed that high HMGB1 and low SASH1 expression correlated with the shortest survival time in patients. But does this axis function in other cancers? The authors evaluated cervix, colon, esophagus, liver, lung, skin, and stomach cancer tissues and found HMGB1 upregulation and SASH1 downregulation in each tumor type when compared to their healthy tissue counterparts, and made similar observations in esophageal carcinoma, head and neck squamous cell carcinoma, stomach adenocarcinoma, and thymoma from database searches.

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Targeting the HMGB1/SET/HAT1-SASH1: Improving Patient Management and Improving Survival?

Overall, the authors demonstrate how high levels of HMGB1 in LUAD facilitate glycolysis and promote metastasis by inhibiting the H3K9 and H3K27 acetylation of the SASH1 tumor suppressor gene promoter and repressing gene expression via the formation of a repressive HMGB1/SET/HAT1 complex. The high HMGB1 expression and low SASH1 expression in LUAD patients with the worst clinical outcomes highlight how this new study may help stratify affected patients and, hence, improve their management. Furthermore, defining the link between the HMGB1/SET/HAT1 complex and increased glycolysis and metastasis may help identify new therapeutic targets and extend patient survival. In conclusion, targeting the HMGB1/SET/HAT1-SASH1 axis appears as a potentially effective means of preventing lung cancer progression.

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About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

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