KR-20260067469-A - Pharmaceutical composition for the prevention or treatment of cancer via modulation of expression of SIRT6

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC) by regulating the expression of Sirtuin 6 (SIRT6). Through in vivo studies, the present invention confirmed that SIRT6 inhibits the proliferation of HCC by inducing autophagy through the regulation of the AMPK-mTOR-TFEB pathway, and that SIRT6 can be usefully utilized to effectively inhibit the proliferation of HCC through overexpression.

Inventors

• 김수미
• 이총삼

Assignees

• 전북대학교산학협력단

Dates

Publication Date

20260513

Application Date

20241105

Claims (10)

1. A pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC) containing SIRT6 (Sirtuin 6) protein as an active ingredient.
2. In paragraph 1, A pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC), characterized in that the above SIRT6 protein comprises the amino acid sequence of SEQ ID NO. 1.
3. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC), characterized by reducing the expression of PARP, caspase-9, or both PARP and caspase-9.
4. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC), characterized by increasing the expression of one or more of uPA, vimentin, and MMP-9.
5. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC), characterized by increasing the accumulation of LC3II.
6. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC), characterized by reducing the expression of p62.
7. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC), characterized by increasing the phosphorylation of AMPK.
8. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC), characterized by reducing the expression of mTOR.
9. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC), characterized by reducing the phosphorylation of S6K.
10. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC), characterized by promoting the migration of TFEB to the nucleus.

Description

Pharmaceutical composition for the prevention or treatment of cancer via modulation of expression of SIRT6 The present invention relates to a pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC) by regulating the expression of Sirtuin 6 (SIRT6). Liver cancer ranks fourth among fatal malignant tumors worldwide and is characterized by a high mortality rate. The major type, accounting for 80–90% of liver cancer cases, is hepatocellular carcinoma (HCC). Over 900,000 new cases of liver cancer are diagnosed annually, and various factors—including age, gender, environment, lifestyle, and underlying liver diseases such as cirrhosis—are reported to influence its development. Despite efforts for early detection and treatment, HCC is known as a disease with a poor prognosis, featuring a high recurrence rate of 70% within five years of treatment and a five-year survival rate of only 38%. Furthermore, HCC is classified as one of the most economically burdensome cancers due to its relatively high resistance to chemotherapy. Therefore, it is essential to explore innovative treatment strategies for HCC. Sirtuin 6 (SIRT6), a member of the sirtuin family, can deacetylate and deliver ADP ribose in a NAD+-dependent manner. SIRT6 is known as a nuclear chromatin-associated protein that plays diverse roles in metabolism, cellular homeostasis, DNA stability, and repair, and is involved in various signaling pathways. SIRT6 can extend the lifespan of mice by suppressing genetic instability, increasing the expression of hepatic gluconeogenesis genes, and enhancing NAD+ synthesis through de novo pathways. Furthermore, SIRT6 can suppress the expression of NF-κB target genes by stimulating the synthesis and release of the inflammatory cytokine TNF-α while simultaneously inhibiting the transcriptional activity of the NF-κB subunit RelA. Given its multifaceted regulatory role in these processes, SIRT6 has garnered attention as a tumor suppressor in several studies. According to a study in the Cancer Genome Atlas, the SIRT6 gene was found to be deleted in 20% of diagnosed cancer cases. In HCC, SIRT6 has been shown to inhibit cellular senescence and promote tumor formation by regulating proliferation and apoptosis through the BCL2-associated X protein-dependent apoptosis pathway. However, conversely, there are also studies indicating that SIRT6 inhibits HCC cell growth by suppressing extracellular signal-regulated kinase signaling pathways. Therefore, the function and mechanism of SIRT6 in HCC remain unclear, and further research into its role and mechanism is necessary. Macroautophagy, also known as autophagy, is a cellular process in which substances destined for degradation or recycling are captured and labeled in bimembrane vesicles called autophagosomes. These structures are transported to lysosomes for further degradation and recycling. Autophagy significantly influences many physiological processes, including lifespan extension, promotion of cell proliferation, adaptation to periods of starvation, and alleviation of oxidative stress. It also plays a crucial role in many diseases, such as Alzheimer's disease, muscle disorders, cardiovascular diseases, and cancer. Various proteins are involved in the regulation of autophagy, among which mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) are known to play important roles. mTOR consists of two distinct complexes: mTORC1 primarily regulates cell growth and protein synthesis, while mTORC2 is activated by growth factors and does not respond to rapamycin. Inhibition of mTORC1 induced by autophagy inhibitors such as rapamycin or periods of nutrient deficiency induces the dephosphorylation of ULK1, ULK2, and Atg13, thereby initiating the autophagy process. AMPK, a protein kinase responsive to changes in adenylate levels, plays a crucial role in maintaining cellular equilibrium by regulating metabolic synthesis and degradation. Thr-172 phosphorylation of the AMPKα subunit is mediated by upstream kinases, particularly LKB1 and Ca2+/calmodulin-dependent protein kinase β, and influences AMPK activity in response to fluctuations in the AMP/ATP or ADP/ATP ratios. While AMPK can directly phosphorylate ULK1, a key protein kinase complex that significantly influences autophagy regulation, reports indicate that mTOR can disrupt the interaction between ULK and AMPK under conditions of sufficient energy supply, suggesting a complex relationship between mTOR and AMPK in cellular regulatory mechanisms. Extensive studies have elucidated the regulatory role of the transcription factor EB (TFEB) in autophagy. AMPK can activate TFEB by inhibiting the action of mTORC1. Several studies have revealed that mTORC1 significantly influences the cytoplasmic sequestration of TFEB and that AMPK plays a crucial role in TFEB transcription. While exploration of TFEB in HCC is limited, recent studies have shown that TFEB-deficient mice experienced more severe