摘要：Hepatocellular carcinoma (HCC) is one of the most frequent human malignancies with poor prognosis. Due to the current limitations of therapeutic options, there is a pressing need to elucidate the molecular mechanisms underlying human hepatocarcinogenesis and to identify novel targets for systemic therapy. It has recently been shown that Deleted in Liver Cancer 1 (DLC1), encoding a RhoGAP (Rho GTPase activating protein), is a tumor suppressor whose allele is lost in ¡« 50% of liver, breast, lung and 70% of colon cancers [1, 2]. Identification of the relevant signaling pathways initiated by DLC1 loss may therefore allow for a more specific and personalized therapy of HCC. Our earlier work showed that DLC1 loss results in constitutive nuclear localization of Megakaryoblastic Leukemia 1 and 2 (MKL1 and 2) proteins, which are coactivators of the transcription factor Serum Response Factor (SRF) governing fundamental biological processes such as cell migration, cell growth, differentiation and cytoskeletal organization [3, 4]. A key feature of MKL1/2 regulation is that the proteins reside in the cytoplasm in an inactive conformation and translocate into the nucleus upon serum stimulation and actin polymerization [5, 6]. MKL1 nuclear localization following DLC1 loss is brought about by activation of the RhoA/actin signaling pathway and impairment of MKL1 phosphorylation, resulting in constitutive activation of tumor-relevant MKL1/2 target genes and enhanced HCC cell proliferation [4]. These findings led us to test whether depletion of MKL1/2 could block the proliferation of DLC1-deficient HCC cells. Indeed, DLC1-deficient HCC cells cease to grow in response to MKL1/2 depletion and display characteristic senescence-associated features including flat morphology, G1 arrest and induction of senescence-associated beta-galactosidase activity [7]. The MKL-knockdown mediated senescence response is caused by activation of the oncogene Ras and results in elevated p16INK4aexpression, hypophosphorylation of the retinoblastoma (Rb) protein and upregulation of components of the senescence-messaging secretome
