Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
FEBS Open Bio. 2022 Sep;12(9):1657-1676. doi: 10.1002/2211-5463.13452. Epub 2022 Jun 24.
Ovarian cancer ranks fifth in terms of cancer mortality in women due to lack of early diagnosis and poor clinical management. Characteristics like high cellular proliferation, EMT and metabolic alterations contribute to oncogenicity. Cancer, being a "metabolic disorder," is governed by various key regulatory factors like metabolic enzymes, oncogenes, and tumor suppressors. Sirtuins (SIRT1-SIRT7) belong to the group of NAD deacetylase and ADP-ribosylation enzymes that function as NAD sensors and metabolic regulators. Among sirtuin orthologs, SIRT6 emerges as an important oncogenic player, although its possible mechanistic involvement in ovarian cancer advancement is still elusive. Our data indicated a higher expression of SIRT6 in ovarian cancer tissues compared with the non-malignant ovarian tissue. Further, we observed that overexpression of SIRT6 enhances glycolysis and oxidative phosphorylation in ovarian cancer cells. The energy derived from these processes facilitates migration and invasion through invadopodia formation by reorganization of actin fibers. Mechanistically, SIRT6 has been shown to promote ERK1/2-driven activatory phosphorylation of DRP1 at serine-616, which has an obligatory role in inducing mitochondrial fission. These fragmented mitochondria facilitate cell movement important for metastases. siRNA-mediated downregulation of SIRT6 was found to decrease cellular invasion through compromised mitochondrial fragmentation and subsequent reduction in stress fiber formation in ovarian cancer cells. Thus, the present report establishes the impact of SIRT6 in the regulation of morphological and functional aspects of mitochondria that modulates invasion in ovarian cancer cells.
由于缺乏早期诊断和临床管理不善，卵巢癌在女性癌症死亡率中排名第五。高细胞增殖、EMT 和代谢改变等特征导致致癌性。癌症作为一种“代谢紊乱”，受多种关键调节因子的控制，如代谢酶、癌基因和肿瘤抑制基因。Sirtuins（SIRT1-SIRT7）属于 NAD 去乙酰化酶和 ADP-ribosylation 酶组，作为 NAD 传感器和代谢调节剂发挥作用。在 Sirtuin 同源物中，SIRT6 作为一种重要的致癌因子出现，尽管其在卵巢癌进展中的可能机制尚不清楚。我们的数据表明，卵巢癌组织中 SIRT6 的表达高于非恶性卵巢组织。此外，我们观察到 SIRT6 的过表达增强了卵巢癌细胞中的糖酵解和氧化磷酸化。这些过程产生的能量通过肌动蛋白纤维的重排促进迁移和侵袭形成侵袭小泡。从机制上讲，SIRT6 已被证明可促进 ERK1/2 驱动的 DRP1 在丝氨酸-616 上的激活性磷酸化，这在诱导线粒体分裂中起必需作用。这些碎片化的线粒体促进了对转移很重要的细胞运动。发现 SIRT6 的 siRNA 介导下调会通过削弱线粒体碎片化和随后减少卵巢癌细胞中应激纤维形成来减少细胞侵袭。因此，本报告确立了 SIRT6 在调节形态和功能方面对线粒体的影响，从而调节卵巢癌细胞的侵袭。
