The role of SIK3 in HER2+ gastric cancer cells

Gastric cancer is one of the leading causes of cancer deaths worldwide and is prevalent in East Asian countries, such as China, Japan, and South Korea, which are known to have high salt diets. The HER2 protein, which is often overexpressed in gastric and breast cancer, plays an important role in signaling for cell growth and proliferation. However, the function of the HER2 in relation to a high salt diet is not yet characterized. Salt has been shown to induce the expression of the SIK3 protein, which is associated with inflammation, tumorigenesis, cellular metabolic changes, and cell-cycle progression. The SIK3 protein is activated by Akt, a downstream protein of HER2, but a direct connection between SIK3 and HER2 has not been clearly defined. A mechanism to characterize this potential relationship begins at HER2 activation of PI3K/Akt, leading to mTORC2 activation, followed by Akt phosphorylation. Then, Akt will activate SIK3, which will phosphorylate HDAC4 and expel it from the nucleus, leading to various cellular processes known to induce cancer. If this mechanism is confirmed, it would offer insight into the synergistic effects of the HER2 protein and a high salt diet, converging on the SIK3 protein to promote cancer survival and progression. Therefore, the inhibition of SIK3 could stop cancer-promoting effects and be a useful target for chemotherapy of HER2+ gastric cancer.