Stabilization of MORC2 by estrogen and antiestrogens through GPER1- PRKACA-CMA pathway contributes to estrogen-induced proliferation and endocrine resistance of breast cancer cells

Abstract

Aberrant activation of estrogen signaling through three ESR (estrogen receptor) subtypes, termed ESR1/ERα, ESR2/ERβ, and GPER1 (G protein-coupled estrogen receptor 1), is implicated in breast cancer pathogenesis and progression. Antiestrogens tamoxifen (TAM) and fulvestrant (FUL) are effective for treatment of ESR1-positive breast tumors, but development of resistance represents a major clinical challenge. However, the molecular mechanisms behind these events remain largely unknown. Here, we report that 17β-estradiol (E2), TAM, and FUL stabilize MORC2 (MORC family CW-type zinc finger 2), an emerging oncoprotein in human cancer, in a GPER1-dependent manner. Mechanistically, GPER1 activates PRKACA (protein kinase cAMP-activated catalytic subunit alpha), which in turn phosphorylates MORC2 at threonine 582 (T582). Phosphorylated MORC2 decreases its interaction with HSPA8 (heat shock protein family A [Hsp70] member 8) and LAMP2A (lysosomal associated membrane protein 2A), two core components of the chaperone-mediated autophagy (CMA) machinery, thus protecting MORC2 from lysosomal degradation by CMA. Functionally, knockdown of MORC2 attenuates E2-induced cell proliferation and enhances cellular sensitivity to TAM and FUL. Moreover, introduction of wild-type MORC2, but not its phosphorylation-lacking mutant (T582A), in MORC2-depleted cells restores resistance to antiestrogens. Clinically, the phosphorylation levels of MORC2 at T582 are elevated in breast tumors from patients undergoing recurrence after TAM treatment. Together, these findings delineate a phosphorylation-dependent mechanism for MORC2 stabilization in response to estrogen and antiestrogens via blocking CMA-mediated lysosomal degradation and uncover a dual role for MORC2 in both estrogeninduced proliferation and resistance to antiestrogen therapies of breast cancer cells.

Morc2a p.S87L mutant mice develop peripheral and central neuropathies associated with neuronal DNA damage and apoptosis

“…The adeno-associated virus could be a candidate for restoration of Morc2a function. However, MORC2 is related to many cancer types ( Pan et al, 2018 ; Yang et al, 2020 ; Zhang et al, 2018 ), so regulating Morc2a gene expression is critical. Thus, gene therapy requires a careful approach, and gene correction with in vivo and ex vivo strategy could be possible.…”

WITHDRAWN: HSPA8 is a New Biomarker of Triple Negative Breast Cancer Associated with Prognosis and Immune Infiltration

“…Furthermore, depletion of HSPA8 could suppress cell growth, induce apoptosis, and cell cycle arrest in solid human tumors [6]. Previous many scholars believe that HSPA8 is involved in tumor molecular chaperone autophagy [7], and participate in the process of breast cancer through molecular chaperone autophagy [8].Nonetheless, the HSPA8 mRNA abnormal expression in TNBC and its diagnostic and prognostic signi cance remains to be elucidated.…”

Chorionic villus-derived mesenchymal stem cell-mediated autophagy promotes the proliferation and invasiveness of trophoblasts under hypoxia by activating the JAK2/STAT3 signalling pathway

“…Recent literature has also explored how STAT3 regulates autophagy and has emphasized that STAT3 affects autophagy in various ways [ 34 ]. Some studies have indicated that STAT3 seems to inhibit autophagy in some types of tumours and infectious diseases [ 35 , 36 ], but others have shown that STAT3 activation can significantly enhance autophagy in some blood tumours and autoimmune and inflammatory diseases [ 37 , 38 ]. STAT3, which responds to a variety of autophagy inducers, is a well-known stress-responsive nuclear factor [ 34 ].…”