SIK2 Is a Centrosome Kinase Required for Bipolar Mitotic Spindle Formation that Provides a Potential Target for Therapy in Ovarian Cancer

Abstract

Summary Regulators of mitosis have been successfully targeted to enhance response to taxane chemotherapy. Here, we show that the Salt Inducible Kinase 2 (SIK2) localizes at the centrosome, plays a key role in the initiation of mitosis and regulates the localization of the centrosome linker protein, C-Nap1, through S2392 phosphorylation. Interference with the known SIK2 inhibitor PKA induced SIK2-dependent centrosome splitting in interphase while SIK2 depletion blocked centrosome separation in mitosis, sensitizing ovarian cancers to paclitaxel in culture and in xenografts. Depletion of SIK2 also delayed G1/S transition and reduced AKT phosphorylation. Higher expression of SIK2 significantly correlated with poor survival in patients with high-grade serous ovarian cancers. These data identify SIK2 as a plausible target for therapy in ovarian cancers.

Identification of salt-inducible kinase 3 as a novel tumor antigen associated with tumorigenesis of ovarian cancer

“…Depletion of c-Src abolished SIK3-indcued cell proliferation; on the other hand, attenuation of p21 Waf/Cip1 expression markedly rescued the G1/S arrest caused by SIK3 depletion in SK-OV3 cells, suggesting that c-Src and p21 Waf/Cip1 are signaling mediators of the SIK3 effect on cell growth. Similarly, more recent one interesting observation reported by Ahmed et al (2010) demonstrated that depletion of another SIK family member, SIK2, caused failure in centrosome separation in mitosis and delayed G1/S transition resulting in the growth suppression in SK-OV3 cells via inactivation of AKT. Moreover, they also showed the molecular profile of SIK2 depletion in mice and correlated high expression of SIK2 with poor survival of patients with highgrade serous ovarian cancers.…”

Reversible Acetylation Regulates Salt-inducible Kinase (SIK2) and Its Function in Autophagy*

“…levels of polyubiquitinated proteins were immunoprecipitated with overexpressed SIK2-KD as compared with SIK2-WT. 5 Furthermore, there is emerging evidence suggesting the critical role of acetylation in autophagy regulation (19 -21). Both p300 and HDAC6, the enzymes controlling SIK2 acetylation, were previously reported as key regulators of autophagy.…”

“…Bricambert et al (4) also showed that SIK2 inhibits ChREBP-mediated hepatic lipogenesis and steatosis in mice through inhibitory phosphorylation of p300 HAT on Ser-89. Furthermore, SIK2 is known to regulate the initiation of mitosis through phosphorylating the centrosome linker protein, C-Nap1 (5). An intimate link between SIK2 and the CREB coactivator TORC1/2 has also been established, particularly in the contexts of melanogenesis (6,7), cerebral ischemia-associated neuronal survival (8), and corticotropin-releasing hormone transcription (9).…”

How to make ovarian cancer cells “sick-too”

“…4 SIK2 is an AMPK-related protein kinase with an established role in the regulation of cell metabolism, and in refeeding from starvation. 5 More recently we revealed a previously unrecognized role of SIK2 for driving ovarian cancer cell metabolism and proliferation at the adipocyte-rich environment of the abdominal cavity.…”