Lung cancer remains the most health threat for its high incidence and mortality rates [1, 2]. Although great efforts have been made in therapy strategies, the prognosis is still poor and the five-year survival rate remains low . Adenylate cyclase-associated protein 1 (CAP1) is an evolutionarily conserved protein that interacts with cofilin and actin to facilitate actin dynamics [4, 5]. Recently, CAP1 was reported to be overexpressed in non-small cell lung cancer tissues and promotes proliferation [6, 7], but the exact role and underlying mechanism of CAP1 in lung cancer progression remains elusive.
It has been reported that both actin and cofilin are required for Pol II-mediated transcriptional elongation. It is well known that actin does not contain a nuclear localization sequence (NLS) and its shuttle from the cytoplasm into the nucleus needs the help with the NLS of cofilin by interaction with cofilin. CAP1 is an important adaptor of cofilin and actin that facilitates cofilin-mediated actin depolymerization . For above convincing supports, CAP1 is believed to shuttle from the cytoplasm into nucleoplasm due to the help with the NLS of cofilin by interaction with cofilin. However, whether CAP1 can also shuttle from the cytoplasm into nucleus, and whether it is involved in RNA Pol II-mediated transcription elongation remains unclear.
In this study, we confirmed that CAP1 is highly expressed in lung cancer tissues and cell lines, which is negatively associated with prognosis in lung cancer patients. Moreover, CAP1 promoted A549 cells proliferation by promoting protein synthesis to accelerate cell cycle progression. Mechanistically, we revealed that CAP1 promotes A549 cell proliferation by accelerating cell cycle progression and increasing protein synthesis, in which CAP1 functions in cofilin-mediated actin dynamics in nucleoplasm by promoting CDK9-mediated Pol II phosphorylation and subsequent transcription elongation. Taken together, our finding suggests that CAP1 is a newly identified protein in regulating RNA polymerases-mediated transcription and our study provides a potential therapeutic target for lung cancer treatment and prognosis prediction.
- Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7-30.
- Larsen JE, Minna JD. Molecular biology of lung cancer: clinical implications. Clin Chest Med. 2011;32:703-40.
- Freeman NL, Chen Z, Horenstein J, Weber A, Field J. An actin monomer binding activity localizes to the carboxyl-terminal half of the Saccharomyces cerevisiae cyclase-associated protein. J Biol Chem. 1995;270:5680-5.
- Moriyama K, Yahara I. Human CAP1 is a key factor in the recycling of cofilin and actin for rapid actin turnover. J Cell Sci. 2002;115:1591-601.
- Xie S, Liu Y, Li X, Tan M, Wang C, Field J, et al. Phosphorylation of the Cytoskeletal Protein CAP1 Regulates Non-Small Cell Lung Cancer Survival and Proliferation by GSK3β. J Cancer. 2018;9:2825-33.
- Kolegova ES, Kakurina GV, Kondakova IV, Dobrodeev AY, Kostromitskii DN, Zhuikova LD. Adenylate Cyclase-Associated Protein 1 and Cofilin in Progression of Non-Small Cell Lung Cancer. Bull Exp Biol Med. 2019;167:393-5.
- Bertling E, Hotulainen P, Mattila PK, Matilainen T, Salminen M, Lappalainen P. Cyclase-associated protein 1 (CAP1) promotes cofilin-induced actin dynamics in mammalian nonmuscle cells. Mol Biol Cell. 2004;15:2324-34.