Abstract
MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling protein with emerging roles in the regulation of DNA damage response and gene transcription, but its mechanistic role in breast cancer development and progression remains unexplored. Here, we show that MORC2 promoted breast cancer invasion and metastasis and these effects depended on a proline-rich domain (PRD) within its carboxy-terminal region spanning residues 601–734. Induced expression of wild-type MORC2 did not significantly affect cell proliferation and cell-cycle progression, but promoted breast cancer cell migration and invasion in vitro and metastatic lung colonization in vivo. The PRD domain was dispensable for the protein stability and subcellular localization of MORC2, but depletion of the PRD domain substantially suppressed MORC2-mediated migration, invasion, and metastasis. Proteomic and biochemical analyses further demonstrated that wild-type MORC2, but not PRD deletion mutant, interacted with catenin delta 1 (CTNND1), a cadherin-associated protein that participates in tumor invasion and metastasis. Moreover, knockdown of endogenous CTNND1 by short hairpin RNAs suppressed the migratory and invasive potential of MORC2-expressing cells. Taken together, these results suggest that MORC2 promotes breast cancer invasion and metastasis through its PRD domain-mediated interaction with CTNND1.
Highlights
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality in women worldwide [1]
Knockdown of endogenous catenin delta 1 (CTNND1) by short hairpin RNAs suppressed the migratory and invasive potential of MORC family CW-type zinc finger 2 (MORC2)-expressing cells. These results suggest that MORC2 promotes breast cancer invasion and metastasis through its proline-rich domain (PRD) domain-mediated interaction with CTNND1
As the functional importance of the PRD domain has been documented in multiple cancer relevant proteins such as p53 (Supplementary Figure 1) [16, 19, 51,52,53,54,55,56], we set out to address the possible functions of the PRD domain in MORC2
Summary
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality in women worldwide [1]. We and others defined MORC2 as a global chromatin remodeler with emerging roles in the regulation of DNA damage response [7] and gene transcription [8, 10, 11]. In addition to its nuclear functions, cytosolic MORC2 is implicated in the regulation of lipogenesis and adipocyte differentiation [12]. Two recent gene expression profiling studies revealed that the expression levels of MORC2 are up-regulated in breast cancer tissues as compared with adjacent normal breast tissues [14] and are associated with recurrence risk of patients with highly aggressive triple-negative breast cancer [15]. The mechanistic role for MORC2 in breast cancer development and progression remains unexplored
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