CATS (FAM64A) abnormal expression reduces clonogenicity of hematopoietic cells

Abstract

The CATS (FAM64A) protein interacts with CALM (PICALM) and the leukemic fusion protein CALM/AF10. CATS is highly expressed in leukemia, lymphoma and tumor cell lines and its protein levels strongly correlates with cellular proliferation in both malignant and normal cells. In order to obtain further insight into CATS function we performed an extensive analysis of CATS expression during differentiation of leukemia cell lines. While CATS expression decreased during erythroid, megakaryocytic and monocytic differentiation, a markedly increase was observed in the ATRA induced granulocytic differentiation. Lentivirus mediated silencing of CATS in U937 cell line resulted in somewhat reduced proliferation, altered cell cycle progression and lower migratory ability in vitro; however was not sufficient to inhibit tumor growth in xenotransplant model. Of note, CATS knockdown resulted in reduced clonogenicity of CATS-silenced cells and reduced expression of the self-renewal gene, GLI-1. Moreover, retroviral mediated overexpression of the murine Cats in primary bone marrow cells lead to decreased colony formation. Although our in vitro data suggests that CATS play a role in cellular processes important for tumorigenesis, such as cell cycle control and clonogenicity, these effects were not observed in vivo.

FAM64A positively regulates STAT3 activity to promote Th17 differentiation and colitis-associated carcinogenesis

“…These results suggest that FAM64A plays important roles in CAC development. Previously, it was shown that FAM64A is up-regulated in various tumor cells and is involved in regulation of cell proliferation, while knockdown of FAM64A inhibits growth of cancer cells in vitro (18,21). In addition, FAM64A is significantly up-regulated in various types of tumor tissues, and high expression of FAM64A is associated with poor survival and clinical outcome, suggesting that FAM64A may be oncogenic in diverse types of cancers and it could be a potential prognostic marker and therapeutic target for cancer (40).…”

“…levels strongly correlate with cell proliferation in both malignant and normal cells (18). FAM64A is a multifunctional protein that is involved in regulation of cell cycle progression, subcellular localization of the leukemogenic fusion protein CALM/AF10, and tumorigenesis (18)(19)(20)(21)(22). In a screen for proteins that regulate STAT3 activity, we identified FAM64A as a positive regulator of STAT3, which modulates binding of STAT3 to the promoters of its target genes.…”

PIMREG (PICALM interacting mitotic regulator)

“…Thus FAM64A plays an important role in determining the kinetics of mitotic progression (Zhao, et al 2008). Although the literature indicates a putative function of FAM64A in controlling cell cycle progression, division and tumorigenesis, the impairment of cell proliferation upon FAM64A depletion was modest and not sufficient to inhibit tumor growth of xenotransplanted U937 cells in an in vivo model (Barbutti, et al 2016). Similarly, the faster metaphase-to-anaphase transition observed in FAM64A depleted cells was not sufficient to produce any of the mitotic defects often observed in cancer cells.…”

“…Likewise, glioblastoma cells induced to proliferate, show a progressive upregulation of FAM64A. Conversely, FAM64A expression drastically decreases when highly proliferative leukemia cells cease to proliferate upon exposure to differentiation agents (Barbutti, et al 2016).Thus, FAM64A expression positively correlates with the proliferative state of the cells (Archangelo, et al 2008). Expression analysis of the murine Fam64a homolog revealed a strong expression throughout mouse embryogenesis, in particular at the developing central nervous system (CNS).…”

“…Based on the fact that levels of FAM64A protein strongly correlate with cellular proliferation in both normal and malignant cells, this protein was described as a marker for proliferation with a possible role in the control of cell proliferation and tumorigenesis (Archangelo, et al 2008). In fact, silencing of FAM64A protein in the U937 leukemia cell line resulted in reduced proliferation and altered cell cycle progression, as attested by diminished expression of the cell cycle regulators CCNA1, CCNE1, CCNB1 (cyclin-A, -E and -B1) in FAM64A depleted cells (Barbutti, et al 2016). Furthermore, Zhao and coworkers described FAM64A as a regulator of chromosome segregation.…”